USPTO Patents Application 10715358

4

1

(12) INTERNATIONAL APPLICATION PUBLlSHEDi^flNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization
International Bureau

(43) International Publication Date
27 June 2002 (27.06.2002)

llliii

PCT

(10) international Publication Number

WO 02/50065 A2

(51) International Patent Classification'': C07D 403/12,

A61K 31/517, 31/519, C07D 401/14, 405/14, 403/14,
417/14, 409/14, 471/04, A61P 35/00

(21) International Application Number: PCT/USO 1/49 140

(22) international Filing Date:

19 December 2001 (19.12.2001)

English
English

(25) Filing Language:

(26) Publication Language:

(30) Priority Data:

60/257,887 21 December 2000 (21.12.2000) US

60/286,949 27 April 2001 (27.04.2001) US

(71) Applicant (for all designated States except US): VERTEX
PHARMACEUTICALS INCORPORATED [USAJS];
Paieni Department, 130 Waveriy Street, Cambridge, MA
02139-4242 (US). "

(72) Inventors; and

(75) Inventors/Applicants (for US only): BEBBINGTON,
David IGB/GBl; 6 linden Close, Newbury. Berkshire
R6141QA (GB), CHARRIER, Jeari-Damien [FR/GBJ;
I Vertex Phamaceuticals Inc., Cottage Wing, Station Road,
j Southam, Bishops Iichinglon, Oxfordshire CV47 2QB
I (GB). DAVIES, Robert [GB/US], 65 Orient Avenue,
I Arlington, MA 02474 (US). EVERITT, Simon [GB/GB];

10 Bell Close, Beaconsfield, Buckinghamshire HP9 lAT
I (GB). KAY, David [GB/GB]; 4 Church Path, Purton,

Wltshire SN5 9DR (GB), KNEGTEL, Ronald [DKA3B];
92 Andersey Way, Abingdon, Wiltshire OX145NW (GB).
PATEL, Sanjay [GB/GBl; 2 Allder Close, Abingdon,
Wiltshire OX14 lYG (GB).

(74) Agents:
cals Inc.
(US).

SILVERMAN, Ian et ah; Vertex Phamiaceuti-
, 130 Waveriy Street, Cambridge, MA 02139^242

(81) Designated States (national): AE, AG, AU AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, ES, H, GB, GD, GE, GH,
GM. HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NO, NZ, PH, PL, PT, RO, RU, SD, SE, SG, SI,
SK, SL, TJ. TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU,
ZA, ZW.

(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, CH, CY, DE, DK, ES, FI, PR,
GB, GR, IE, IT, LU, MC. NL, PT, SE, TR), OAPI patent
(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR.
NE, SN, TD. TG).

Published:

— without international search report and to be republished
upon receipt of that report

For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.

(54) Title: PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS

^ (57) Abstract: This invention describes novel pyrazole compound of formula He:

^ 2 wherein R» is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8- 10

2- r membered bicyclic ring selected from aryl. helCToaryl, heterocyclyl or caibocyclyl;

^ R \^-:^5\ R" and Ry are taken logetherwith their intervening atoms to form a fused, unsaturated

O I or partially unsaturated, 5-7 membered ring having 0-3 heteroatoms; and R^ and R^'

O WM-''''^N are as described in the specification. The compounds are useful as protein kinase

^ \ (I Ic) inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such

'^'^^^v^^'^N ^ cancer, diabetes and Alzheimer* s disease.

o

11

H

PYRAZOLE COMPOTOIDS USEFUL AS PROTEIN KINASE INHIBITORS

CROSS REFERENCE TO RELATED M>PLI CATIONS
This application claims priority to US
Provisional Patent Application 60/257, 887 filed December
21, 2000 and US Provisional Patent Application 60/286 , 949
filed April 27, 2001, the contents of which are
incorporated herein by ref erence .

FIELD OF THE INVENTION
The present invention is in the f ield of
medicinal chemistry and relates to compounds that are
protein kinase inhibitors, compositions containing such
compounds and methods of use. More particularly, this
invention relates to compounds that are inhibitors of
Aurora-2 protein kinase. The invention also relates to
methods of treating diseases associated with protein
kinages, especially diseases associated with Aurora-2,
such as cancer.

BACKGROUND OF THE INVENTION
The search for new therapeutic agents has been
greatly aided in recent years by better understanding of
the structure of enzymes and other biomolecules
associated with target diseases. One important class of
enzymes that has been the subject of extensive study is
the protein kinases .

Protein kinases mediate intracellular signal
transduction. They do this by ^f f-ecting a phosphoryl
transfer from a nucleoside triphosphate to a prot-ein
acceptor that is involved in a signaling pathway. There
are a number of kinases and pathways through which

extracellular and other stimuli cause a variety of
cellular responses to occur inside the cell- Exan4>les of
such stimuli include environmental and chemioal stress
signals (e.g. osmotic shock, heat shock, ultraviolet
radiation, bacterial endotoxin, H2O2) , cytokines (e-g-
interleukin-1 (IL-l) and tumor necrosis factor a (TNF-
a) ) , and growth factors (e.g- granulocyte maorophage-
colony- stimulating factor (GM-CSF) , and fibroblast growth
factor .(FGF) . An extracellular stimulus may effect one
or more cellular responses related to cell growth,
migration, differentiation, secretion of hormones,
activation of transcription factors, muscle contraction,
glucose metabolism, control of protein synthesis and
regulation of cell cycle.

Many diseases are associated ^ith abnormal
cellular responses triggered by protein kinase -mediated
events. These diseases include autoimmune diseases,
inflammatory diseases, neurological and neurodegenerative
diseases, cancer, cardiovascular diseases, allergies and
asthma, Alzheimer's disease or hormone -related diseases.
Accordingly, there has been a substantial effort in
medicinal chemistry to find protein kinase inhibitors
that are effective as therapeutic agents.

Aurora- 2 is a serine/ threonine p3?otein kinase
that has been implicated in human cancer, such as colon,
breast and other solid tumors. This kinase is believed
to be involved in protein phosphorylation events that
regulate the cell cycle. Specifically, Aurora-2 may play
a role in controlling the accurate segregation of
chromosomes during mitosis. Misregulation of the cell
cycle can lead to cellular proliferation and other
abnormalities. In human colon cancer tissue, the aurora-
2 protein has been found to be overexpressed . See

-3-

Bischoff et al./EMBO J., 1998, 17, 3052-3065; Schumacher
et al*, i7. Cell Biol., 1998, 143, 1635-1646; Kimiira et
al,, J. Biol. ChGia., 1997, 272, 13766-13771 •

Glycogen synthase kinase-3 {GSK-3) is a
5 serine/ threonine protein kinase comprised of a and p

isoforms that, are each encoded by distinct genes [Coghlan
et al., caiemistry & Biology, 1, 793-803 (2000); Kim and
Kimmel, Cutt. Opinion Genetics Dev. , 10, 508-514 (2000)].
GSK-3 has been implicated in various diseases including

10 diabetes, Alzheimer's disease, CNS disorders such as

manic depressive disorder and neurodegenerative diseases,
and cardioraypcete hypertrophy [WO 99/65897; WO 00/38675;
and Haq et al., jr. Cell Biol. (2000) 151, 117]. These
diseases may be caused by, or result in, the abnormal

15 operation of certain cell signaling pathways in which
GSK-3 plays a role. GSK-3 has been found to
phosphorylate and modulate the activity of a number of
regulatory proteins. These proteins include glycogen
synthase which is the rate limiting enzyme necessary for

20 glycogen synthesis, the ' microtubule associated protein
Tau, the gene transcription factor P-catenin, the
translation initiation factor elF2B, as well as ATP
citrate lyase, axin, heat shock factor- 1, c-Jun, c-Myc,
c-Myb, CREB, and CEPBa. These diverse protein targets

25 implicate GSK-3 in many aspects of cellular meted^olism,
proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant
for the treatment of type II diabetes, insulin- induced
signaling leads to cellular glucose uptake and glycogen

30 synthesis. Along this pathway / GSK-3 is a negative .

regulator of the insulin- induced signal. Normally, the
presence of insulin causes inhibition of GSK-3 mediated

phosphorylation and deactivation of glycogen synthase.
The inhibition of GSK-3 leads to increased glycogen
synthesis and glucose uptake [Klein et al., PHAS, 93,
8455-9 (1996); Cross et al.^ Sloclienj. »7., 303, 21-26
5 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993);
Massillon et al., Blochem J. 299, 123-128 (1994)1.
However, in a diabetic patient where the insulin response
is impaired, glycogen synthesis and glucose uptake fail
to increase despite the presence of relatively high blood

10 levels of insulin. This leads to abnormally high blood
levels of glucose with acute and long term effects that
may ultimately result in cardiovascular disease, renal
failure and blindness. In such patients, the normal
insulin- induced inhibition of GSK-3 fails to occur. It

15 has also been reported that in patients with type II
diabetes, GSK-3 is overexpressed [WO 00/38675] .
Therapeutic inhibitors of GSK-3 therefore are considered
to be useful for treating diabetic patients suffering
from an impaired response to insulin.

20 GSK-3 activity has al^o been associated with

Alzheimer's disease. This disease is characterized by
the well-known P-amyloid peptide and the formation of
intracellular neurofibrillary tangles. The
neurofibrillary tangles contain hyperphosphorylated Tau

25 protein where Tau is phosphorylated on abnormal sites.
GSK-3 has been shown to phosphorylate these abnormal
sites in cell and animal models. Furthermore, inhibition
of GSK-3 has been shown to prevent hyperphosphoiylation
of Tau in cells [Lovestone et al.. Current Biology 4,

30 1077-86 (1994); Brownlees et al., Neuroreport B, 3251-55
(1997)]. Therefore, it is believed that GSK-3 activity
may promote generation of the neurofibrillary tangles and
the progression of Alzheimer's disease.

-5-

Another substrate of GSK-3 is p-catenin whicdi
is degradated after phosphorylation by GSK-3 . Reduced
levels of p-catehin have been reported in schizophrenic
patients and have also been associated with other
5 diseases related to increase in neuronal cell death

[Zhong et al-. Nature, 395, 698-702 (1998); Takashima -et
al., PNAS, 90, 7789-93 (1993); Pei et al • , J.
Neuropathol . Exp, 56 , 70-78 (1997)].

As a result of the biological importance of

10 GSK-3, there is current interest in therapeutically

effective GSK-3 inhbitors. Small molecules that inhibit
GSK-3 have recently been reported [WO 99/65897 (Chiron)
and WO 00/38675 (SmithKline Beecham) ]

For many of the aforementioned di-seases

15 associated with abnormal GSK-3 activity, other protein
kinases have also been targeted for treating the same
diseases. However, the various protein kinases of ten act
through different biological pathways. For example,
certain quinazoline derivatives have been reported

20 recently as inhibitors of p38 kinase (WO 00/12497 to
Scios) . The compounds are reported to be useful for
treating conditions characterized by enhanced p38-a
activity and/ or enhanced TGF-p activity. While p38
activity has been implicated in a wide variety of

25 diseases, including diabetes, p38 kinase is not reported
to be a constituent of an insulin signaling pathway that
regulates glycogen synthesis or glucose uptake.
Therefore, unlike GSK-3, p38 inhibition would not be
expected to enhance glycogen synthesis and/or glucose

30 uptake.

There is a continued need to find hew
therapeutic agents to treat human diseases. The protein

V

-6-

kinases Aarora-2 and GSK-3 are especially attractive
targets for the discovery of new therapeutics due to
their important roles in cancer and diabetes,
respectively.

5

DESCRIPTION OF THE INVENTION
It has now been found that compounds of this
invention and pharmaceutical compositions thereof are
effective as protein kinase inhibitors, particularly as
10 inhibitors of Aurora- 2. These compounds have the general
formula I:

20

or a pharmaceutically acceptable derivative or prodihig
thereof, wherein:

is nitrogen or C-R® and is nitrogen or CH, wher-ein
15 at least one of ^ amd Z^ is nitrogen;

R* and R^ are independently selected from T-R^ or L-Z-R^,
or R"^ and R^ are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, -sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by R"" and R^ is independently substituted
by oxo, T-R^, or L-Z-R^, and each substitutable ring

nitrogen of said ring formed by R'^ and is

independently siibstituted by R*;
Q is selected from -N(R*)-, -0-, -C(R^')2-# 1#2-

cyclopropanediyl, 1, 2-cyclobutanediyl, or 1,3-

cyclobutanediyl ;
R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membei?ed
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaiiyl or
heterocyclyl ring having 1-4 ring heteroatoms. selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and ^ach
substitutable ring nitrogen of Ring D is independently
substituted by -R^;

T is a valence bond or a C1-4 alkylidene chain, wherein
when Q is -C(R^')2-, a methylene unit of said C1-4
alkylidene chain is optionally replaced by -0-, -S-,
- -N(R*)-, -CO-, -CONH-, -NHCO-, -SO2-, -SO2NH-, -NHSO2-/
-CO2-, -0C(0)-, -OC(0)NH-, or -NHCO2-;

Z is a Ci-4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -SOsNCR^)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C(0)0-,
-N(R^)CON(R«)-, -N(R^)S02N(R^)-, -N (R^)N (R^) - ,
-C(0)N(R^)-, -0C(O)N(R^)-, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R«)2S02-/ "C(R^)2S02N(R^)-, -C (R^)2N-(R^) - ,
-C(R^)2N(R«)C(0)-, -C(R^)2N(R^)C(0)0-, -C (R^) =NN(R«) -,
-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C(R^)2N(R^) S02N{R^) -, or
-C(R^)2N(R^)CON(R^) -;

R^ and R^' are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms

selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by

auid R^' is independently sxabstituted by halo, oxo,
-car, -NO2, -R'/ or -V-R*, and each substitutable ring
5 nitrogen of said ring -formed by R* and R*' is
independently substituted by R*;
r' is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COCH2COR, .-NO2, -CN, -S(0)R, -S(0)2R/ -SR,
-N(R*)2, tC0N(R'')2, -S02N(R')2, -OC(=0)R, -JH (R')COR,
10 -N(R')C02(Ci.6 aliphatic) , -N{R*)N(R*> 2, -C=NN(R*)2,

-C=N-OR, -N{R')CON(R'')a, -N(R'')S0aN(R'')2# -N(R*)S02R, or
-0C(=0)N(R')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-6
15 aliphatic, Cg-io aryl, a heteroaryl ring having 5-10

ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ;

each R* is independently selected from -R"', -COR',

-CO2 (optionally soibstituted Ci-e aliphatic) , -CONCR'ja,

20 or -SO2R';

each R^ is independently selected from -R, halo, -OR,
-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R^)2, -CON(R^)2, -S02N(R*)2, -0C(=O)R, -N(R*)COR,
-N(R*) CO2 (optionally stabstituted Ci-e aliphatic),

25 -N(R*)N(R*)2, -C=NN(R*)2, -C=N-OR, -N (R*) CON (R*)2,

-N(R'*)S02N(R^)2/ -N(R'*)S02R, or -OC (=0) N (R^) 2 ;
V is -d-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R*)-,
-N(R*)-, -CO-, -CO2-, -N(R^)CO-, -N(R*)C(0)0-,
-N(R*)CON(R^)-, -N(R^)S02N(R^)-, -N(R^)N(R^)-,

30 -C(0)N(R*)-, -OC(0)N(R*)-, -C(R^)20-, -C(R*)2S-,

-C(R*)2S0-, -C(R^)2S02-, -C(R*)2S02N(R®)-, -C (R*) 2N (R*) - ,
-C(R*)2N(R*)C{0)-; -C(R*)2N(R*)C(0)O-, -C (R*) =NN(R«)

-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C(R^)2N(R^) SOgNCR^) or
-C{R^)2N(R^)CON(R^)

W is -C(R^)20-, -C(R^)2S-, -C{R^)2SO-, -C(R^)2S02-,
-C{R^)2S02N(R^)-, -C(R^)2N(R^)-, -CO-. -CO2-/
-C(R^)OC(p)-, ~C(R^)OC(0)N(R^)-, -C(R^)2N(R^)C0-,
-C{R^)2N(R^)C(0)0-, -C(R^)=NN(R^)-, -C (R^) =N-0- ,
-C(R^)2N(R^)N(R^)-, -C(R^)2N(R^)S02N(R^)-,
-C(R^)2N(R^)CON{R^) -, or -CON{R^)-;

each is independently selected from hydrogen or an
optionally siabstituted C1-4 aliphatic group, or two R^
groups on the same nitrogen atom may be taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;

each R^' is independently selected from hydrogen or a C1-4
aliphatic group, or two R^' on the same oarbon atom ar^e
taken together to form a 3-6 membered carbocyclic ring;

each r'^ is independently selected from hydrogen or an
optionally sxabstituted Ci-e aliphatic group, or two r'^
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and

R® is selected from -R, halo, -OR, -C(=0)R, -CO2R, -COCOR,
-NO2/ -CN, -S(0)R, -SO2R, -SR, -N(R^)2, -CON(R*)2/
-S02N{R^)2. -OC(=0)R, -N(R^)COR, -N(R^)C02 (optionally
substituted Ci-6 aliphatic), -N(R*)N(R^) 2/ -C=NN(R*)2.
-C=N-OR, -N{R*)CON{R*)2,. "N(R*)S02N(R*)2, -N(R*)^02R, or

-0C(=0)N(R*)2-

As used herein, the following definitions shall
apply "Unless otherwise indicated. The phrase '^optionally
substituted" is used interchangeably with the phrase
* substituted or lansubstituted* or with the term
^ (uh) substituted." Unless otherwise indicated, an
optionally substituted group may have a substituent at

-10-

each substitutable position of the group / and each
STibstitution is independent of the other.

The term '^aliphatic" as used herein means
straight-chain, branched or cyclic C1-C12 hydrocarbons
5 which are completely saturated or which contain one or
more units of unsaturation but which are not aromatic.
For example, suitable aliphatic groups include
substituted or unsubstituted linear, branched or cyclic
alkyl, alkenyl, alkynyl groups and hybrids thereof such

10 as (cycloalkyl) alkyl, (cycloalkenyl ) alkyl or

(cycloalkyl) alkenyl. The terms ^alkyl'', ^alkoxy",
^^hydroxyalkyl" , ^alkoxyalkyl" , and ^alkoxycarbonyl" , used
alone or as part of a larger moiety includes both
straight and branched chains containing one to twelve

15 carbon atoms. The terms ^^alkenyl" and '^alkynyl" used
alone or as part of a larger moiety shall include both
straight and branched chains containing two to twelve
carbon atoms. The term cycloalkyl'' used alone or as
part of a larger moiety shall include cyclic C3-C12

20 hydrocarbons which are completely saturated or which

contain one or more units of unsaturation, but which are
- ' not aromatic.

The terms ^^haloalkyl'' , **haloalkenyl'' and
^^haloalkoxy" means alkyl, alkenyl or alkoxy, as the case

25 may be, substituted with one or more halogen atoms. The
term "halogen" means F, CI, Br, or I.

The term "heteroatom" means nitrogen, oxygen,
or sulfur and includes any oxidized form of nitrogen and
sulfur, and the quatemized form of any basic nitrogen.

30 Also the term "nitrogen" includes a substitutable

nitrogen of a heterocyclic ring. As an example, in a
saturated or partially unsaturated ring having 0-3
heteroatoms selected from oxygen, sulfur or nitrogen, the

-11-

nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl) , NH (as
in pyrrol idinyl) or NR* (as in N- slabs tituted
pyrrolidinyl) .

The terms ^carbocycle" , '^oarbocyclyl" ,
5 ''carbocyclo" , or '^carbocyclic*' as used herein ineans an
aliphatic ring system having three to fourteen members.
The terms ^carbocycle" , ^^carbocyclyl'' , ^carbocyclo*' , or
^'carbocycliC whether saturated or partially unsaturated,
also refers to rings that are optionally stobstituted.

10 The terms ^^carbocycle" , "carbocyclyl*' , "carbocyclo" , or

^carbocyclic" also include aliphatic rings that are fused
to one or more aromatic or nonaromatic rings, such as in
a decahydronaphthyl or tetrahydronaphthyl , where the
radical or point of attachment is on the aliphatic ring.

15' The temca "^aryl" used alone or as part of a

larger moiety as in ^^aralkyl" , ^aralkoxy" , or
^^aryloxyalkyl" refers to aromatic ring groups having
five to fourteen members, such as phenyl, benzyl,
phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-

20 anthracyl. The term ^aryl" also refers to rings that are
optionally substituted. The term ^aryl" may be used
interchangeably with the term ^^aryl ring". ^^Aryl" also
includes fused polycyclic aromatic ring systems in which
an aromatic ring is fused to one or more rings. Examples

25 include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-

anthracyl . Also included within the scc^e of the term
'^aryl", as it is used herein, is a group in which an
aromatic ring is fused to one or more non- aromatic rings,
such as in an indanyl, phenanthridinyl, or

30 tetrahydronaphthyl, where the radical or point of
attachment is on the aromatic ring.

The term ^heterocycle" , '^heterocyclyl" , or
^heterocyclic" "^as used herein includes non-aromatic ring

-12-

systems having five to fourteen members, preferably five
to ten, in which one or more ring carbons, preferably one
to four, are each replaced by a heteroatom such as N, O,
or S. Examples of heterocyclic rings include 3-lH-
5 ben2imidazol-2.-one, (1-siabstituted) -2-oxo-benzimidazol-3-
yl , 2 - te t rahydrof urany 1 , 3 - te t rahydrof uranyl , 2 -
tetrahydropyranyl, 3-tetrahydropyranyl, 4-
tetrahydropyranyl, [1,3] -dioxalanyl, [1, 3].-dithiolanyl,
[1,3]- dioxanyl , 2 - 1 e t rahydrothiophenyl , 3 -

1 0 tetrahydrothiophenyl , 2 -morpholinyl , 3 -morpholinyl , 4 -
morpholinyl, 2-thiomorpholinyl , 3-thiomo2:pholinyl, 4-
thiomorpholinyl , 1 -pyrrolidinyl , 2 -pyrrolidinyl , 3 -
pyrrolidinyl, 1-piperazinyl, 2~piperazinyl, 1-
piperidinyl , 2 -piperidinyl , 3 -piperidinyl , 4 -piperidinyl ,

15 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl/ 1-
phthalimidinyl , benzoxanyl , benzopyrrolidinyl ,
benzopiperidinyl, benzoxolanyl , benzothiolanyl , and
benzothianyl . Also included within the scope of the term
^heterocyclyl" or ^heterocyclic" , as it is used herein,

20 is a group in which a non-aromatic heteroatom-containing
ring is fused to one or more aromatic or non- aromatic
rings, such as in an indolinyl, chromanyl,
phenanthridinyl , or tetrahydroquinolinyl, where the
radical or point of attachment is on the non- aromatic

25 heteroatom-containing ring- The term ^^heterocycle" ,

^heterocyclyl" , or ^^heterocyclic" whether saturated or
partially unsaturated, also refers to rings that are
. optionally siabstituted.

The term ^^heteroaryl*" , used alone or as pari: of

30 a larger moiety as in ^heteroaralkyl" or

'^heteroarylalkoxy'' , refers to heteroaromatic ring groups
having five to fourteen members. Examples of heteroaryl
rings include 2 -f uranyl, 3-furanyl, 3-furazanyl, N-

-13-

imidazolyl/ 2-imida2olyl, 4-imida2olyl, S-imidazolyl, 3-
isoxazolyl/ 4-isoxa2olyl, 5-isoxazolyl, 2-oxadiazolyl, 5-
oxadiazolyl, 2-oxazolyl/ 4-oxazolyl, 5-oxazolyl, 1-
pyrrolyl, 2-pyrrolyl^ 3-pyrrolyl, 1-pyrazolyl, 2-
5, pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl/ 4-pyridyl,
2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-
thiazolyl/ 4-thiazolyl, 5-thiazolyl, B-tetrazolyl, 2-
triazolyl, 5-^triazolyl, 2-thienyl,- 3-thienyl, carbazolyl,
benzimidazolyl , benzothienyl , benzof uranyl , indolyl,

10 quinolinyl, benzotriazolyl, benzothiazolyl ,

benzooxazolyl , benzimidazolyl , isoquinolinyl , indazolyl ,
isoindolyl, acridinyl, or benzoisoxazolyl . Also included
within the scope of the term ^heteroaryl" , as it is used
herein, is a group in which a heteroatomic ring is fused

15 to one or more aromatic or nonaromatic rings where the
radical or point of attachment is on the heteroaromatic
ring. Examples include tetrahydroquinolinyl ,
tetrahydroisoquinolinyl, and pyrido [3,4-d]pyrimidinyl.
The term ^heteroaryl" also refers to rings that are

20 optionally substituted. The term ^heteroaryl" may be

used interchangeably with the term **heteroaryl ring" or
the term ^heteroaromatic'' .

An aryl (including aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including

25 heteroaralkyl and heteroaryl alkoxy and the like) group
may contain one or more sxabstituents . Examples of
suitable substituents on the unsaturated carbon atom of
an aryl, heteroaryl/ aralkyl, or heteroaralkyl group
include a halogen, -R**, -OR**, -SR**, 1, 2-methyl^e-dioxy,

30 1,2 -ethyl enedioxy, protected OH (such as acyloxy) , phenyl
(Ph) , substituted Ph, -O(Ph), substituted -O(Ph),
-CH2(Ph), substituted -CHaCPh), -CH2CH2(Ph), substituted
-CH2CH2(Ph), -NO2. -CN, -N(R*')2, -NR^'CKO) R*^, .NR**C<0)N(R**) 2/

-14-

-NR°C02R°, -NR*l!IR*C(0)R'', -NRniR^C (O)N(R') 2, -NRniR^COaR" /
-C{0>C(0)R'', -CCOCHaCCOR", -COaR", -C<0)R'», -C{0)N<R*')2,
-OCCONCR^ya, -S(0)2R°, -S02N<R"')2, -S<0)R'', -NR''S02N(R*') 2,
-NR°S02R°, -C(=S)N(R°)2, -C (=NH) -N (R°) 2 , - (CH2)yNHCK0)R*',
5 - (CH2)yNHC(C»CH(V-R°) (R") ; wherein «acli R° is independently
selected from hydrogen, a substituted or unsubstituted
aliphatic group, an vmsvibstituted heteroaryl or
heterocyclic ring, phenyl (Ph) , substituted Ph, -0<Ph) ,
substituted -b(Ph) , -CH2(Ph), or substituted -CH2(Ph); y

O io is 0-6; and V is a linker group. Examples of

STJbstituents on the alijrfiatic group or the phenyl ring of
R*» include amino, alkylamino, dialJcylamino, aminocarbonyl ,
halogen, alkyl, alkylaminocarbonyl , dialkylaminocarbonyl ,
alkylaminocarbonyloxy, diallqrlaminocafbonyloxy, alkoxy,
15 nitro, cyano, carboxy, alkoxycarbonyl , alkylcarbonyl ,
hydroxy, haloalkoxy, or haloalkyl.

An aliphatic group or a non-aromatic
heterocyclic ring may contain one or more sxibstituents .
Examples of sviitable svibstituents on the saturated carbon
20 of an aliphatic group or of a non-aromatic heterocyclic

C-j ring include those listed above for the unsaturated

carbon of an aiyl or heteroaryl group ^d t:he following:
=0, =S, =NNHR*, =NN(R*)2, =N-, =NNHC(0)R*, =NNHC02 (alkyl) ,
=NNHS02 (alkyl) , or =11R*, where each R* is independently
25 selected from hydrogen, an \jnsubstituted aliphatic group
or a substituted aliphatic group. Examples of
substituents on the aliphatic group include amino,
alkylamino, dialkylamino, aminocarbonyl , halogen, alkyl,
alkylaminocarbonyl, dialkylaminocarbonyl ,
30 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy,
nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl,
hydroxy, haloalkoxy, or haloalkyl.

-15-

Suitable substituents on the nitrogen of a non-
aromatic heterocyclic ring include -N(R'^)2# -C(0)R*,
^COzR*, -C(0)C(0)R*, -C(0)CH2C(0)R*, -SO2R*, -S02N(R*)2.
-C(=S)N(R*)2/ -C{=NH)-N(R*)2, and -NR^SOaR*; wherein each R*
5 is independently selected from hydrogen, an aliphatic
group / a substituted aliphatic group, phenyl (Ph) ,
substituted Ph/ -0{Ph), substituted -O(Ph) , CH2(Ph),
substituted cai2 (Ph) , or an unsubstituted heteroaryl or
heterocyclic ring- Examples of. substituents on the

10 aliphatic group or the phenyl ring include amino,

alkylamino, dialkylamino, aminocarbonyl , halogen, alkyl,
alkylaminocarbonyl , dialkylaminocarbonyl ,
alkyl aminocarbonyloxy , dialkylaminocarbonyloxy , alkoxy ,
nitro, cyano, carboxy, alkoxycarbonyl , alkylcarbonyl ,

15 hydroxy, haloalkoxy, or haloalkyl.

The term ^linker group" or ^linker*' means an
organic moiety that connects two parts of a compound.
Linkers are typically comprised of an atom such as oxygen
or sulfur, a unit such as -NH-, -CH2- , -C (O) - , -C(0)NH-,

20 or a chain of atoms, such as an alkylidene chain. The
molecular mass , of a linker is typically in the range of
about 14 to 200, preferably in the range of 14 to 96 with
a length of up to about six atoms. Examples of linkers
include a saturated or vmsaturated Cx-€ alkylidene chain

25 which is optionally substituted, and wherein one or two

saturated carbons of the chain are optionally replaced by
-C(0)-, -C(0)C(0)-, -CONH-, -CONHNH-, -CO2-, -0C(0)-,
-NHCO2-, -0-, -NHCONH-, -OC{0)NH-, -NHNH-, -NHCO-,
-SO-, -SO2-, -NH-, -SO2NH-, or -NHSO2-.

30 The term ^^alkylidene chain'' refers to an

optionally s\ibstituted, straight or branched carbon chain
that may be fully saturated or have one or more units of

unsaturation. The optional substituents are as described
above for an aliphatic group.

A combination of substituents or variables is
permissible only if such a <:otnbination results in a
stable or chemically feasible compoiind, A stable
compound or chemically feasible oomppund is one in which
the chemical structure is not substantially altered when
kept at a temperatxire of 40 "^C or less, in the absence of
moisture or other chemically reactive conditions, for at
least a week.

Unless otherwise stated, structures depicted
herein are also meant to include all stereochemical forms
of the structure; i.e., the R and S configurations for
each asymmetric center. Therefore, single stereochemical
isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of
the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds which
differ only in the presence of one or more isotopically .
enriched atoms. For example, compounds having the
present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of
a carbon by a ^^C- or ^^C-enriched carbon are within the
scope of this invention.

Con5>ounds of formula I or salts thereof may be
formulated into compositions. In a preferred embodiment,
the composition is a pharma<:euti<:al composition. In one
embodiment, the composHzion comprises an amount of -the
protein kinase inhibitor effective to inhibit a protein
kinase, particularly Aurora-2, in a biological sample or
in a patient- Compounds of this invention and
pharmaceutical compositions thereof, whi-ch comprise an
amount of the protein kinase inhibitor effective to treat

-17-

or prevent an Aurora -2 -mediated condition and a
pharmaceutically acceptable carrier^ adjuvant , or
vehicle, may be formulated for administration to a
patient.

5 Another aspect of this invention relates to a

method of treating or preventing an Aurora -2 -mediated
disease with an Aurora -2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amoxmt of a
10 con^oimd of formula I or a pharmaceutical composition
thereof .

The term "Aurora- 2 -mediated* disease" or
"Aurora- 2 -mediated condition", as used herein, means any
disease or other deleterious condition in which Aurora is

15 known to play a role. The terms "Aurora- 2 -mediated

disease" or "Aurora- 2 -mediated condition" also mean those
diseases or conditions that are alleviated by treatment
with an Aurora-2 inhibitor. Such conditions include,
without limitation, colon, breast, stomach, and ovariaii

20 cancer.

Another aspect of the invention relates to
inhibiting Aurora-2 activity in a biological san5>le,
which method comprises contacting the biological sample
with the Aurora-2 inhibitor of formula I, or a

25. composition thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula I or a composition comprising said

30 compound.

Another aspect of this invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK- 3 inhibitor, which method conqorises

-18-

administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
X or a pharmaceutical composition thereof.

The terms "GSK- 3 -mediated disease" or "GSK-3-

.5 mediated condition", as used herein, mean any disease or
other deleterious condition or states in which GSK-3 is
Imown to play a role. Such diseases or conditions
include, without limitation,^ diabetes, Alzheimer's
disease, Huntington's Disease, Parkinson's Disease, AIDS-

10 associated dementia, amyotrophic lateral sclerosis (AML) ,
multiple sclerosis (MS) , schizophrenia, cardiomycete
hypertrophy, regerfusion/ ischemia, and baldness.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering

15 blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amoxant of a compound of formula
1 or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another

20 method relates to inhibiting the production of

hyperphosphorylated Tau protein, which is useful in
halting or slowing the progreission of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for

25 treating schizophrenia. .

Another aspect of the invention relates to
inhibiting GSK-3 activity in a biological sample, which
method comprises contacting the biological san5>le with a
GSK^3 inhibitor of formula I.

30 Another aspect of this invention relates to a

method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compoxand
of formula 1 or a composition comprising said compoiind.

-19-

Another aspect of this invention relates to a
method of treating or preventing a CDK-2 -mediated disease
with a CDK-2 inhibitor^ which method coitprises '
administering to a patient in need of such a treatment a
5 therapeutically effective amotint of a compoiond of formula
X or a pharmaceutical composition thereof.

The terms "CDK-= 2 -mediated disease" or "CDK-2-
mediated condition", as used herein, mean any disease or
other deleterious condition in which CDK-2 is known to

10 play a role. The terms "CDK-2 -mediated disease" or "CDK-

2 -mediated condition" also mean those diseases or >
conditions that are alleviated by treatment with a CDK-2
inhibitor. Such conditions include, without limitation,
cancer, Alzheimer's disease, restenosis, angiogenesis,

15 glomerulonephritis, cytomegalovirus, HIV, herpes,

psoriasis, atherosclerosis, alopecia, and autoimmune
diseases such as rheumatoid arthritis. See Fischer, P.M.
and Lane, D.P., Current Medicinal Chemistjry, 1, 1213-1245
(2000); Mani, S., Wang, C, Wu, K. , Francis, R. -md

20 Pestell, R. , Exp. Opin. Invest, Drugs, 9, 1849 (2000);
Fry, D.W- and Garrett, M.D., Current Cfpxnlon in
Oncologic, Endocrine & Metabolic Investigational Drugs,
2, 40-59 (2000).

Another aspect of the invention relates to

25 inhibiting CDK-2 activity in a biological sample or a
patient, which method comprises admini-stering to the
patient a compotmd of formula I or a composition
comprising said compound.

Another aspect of this invention relates to a

3 0 method of treating or preventing an ERK- 2 -mediated

diseases with an ERK- 2 inhibitor, which method comprises
administering to a patient in need of such a treatment a

-20-

therapeutically effective amount of a compoiind of formula
I or a pharmaceutical composition thereof.

The terms «ERK-mediated disease" or ^^ERK-
mediated condition", as used herein mean any disease or
5 other deleterious condition in which ERK is known to play
a role- The terms "ERK- 2 -mediated disease" or ^^ERK-2-
mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a ERK-2
inhibitor. Such conditions include, without limitation,

10 cancer, stroke, diabetes, hepatomegaly, cardiovascular
disease including cardiomegaly, Alzheimer's disease,
cystic fibrosis, viral disease, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic
disorders including asthma, inflammation, neurological

15 disorders and hormone -related diseases. The tearo

"cancer" includes, but is not limited to the following
cancers: breast', ovary, cervix, prostate, testis,
genitourinary tract, esophagus, larynx, glioblastoma,
neuroblastoma, stomach, skin, keratoacaoxthoma , lung,

20 epidermoid carcinoma, large cell carcinoma, small cell
carcinoma, lung adenocarcinoma, bone, colon, adenoma,
pancreas, adenocarcinoma, thyroid, follicular carcinoma,
iindif ferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver

25 carcinoma and biliary passages, kidney carcinoma, myeloid
disorders, lymphoid disorders, Hodgkin's, hairy cells,
buccal cavity and pharynx (oral) , lip, tongue; mouth,
pharynx, small intestine, colon-rectum, large intestine,
rectum, brain and central nervous system, and leukemia.

30 ERK-2 protein kinase and its implication in various
diseases has been described [Bokemeyer et al. 1996,
Kidney Jnt. 49, 1187; Anderson et al., 1990, Nature 343,
651; Crews et al., 1992, Science 258, 478; Bjorbaek et

-21-

al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994,
Cell IB, 1027; Raingeaud et al., 1996, Mol. Cell Biol.
16, 1247; Raingeaud et al* 1996; Clien et al., 1993 Proc.
Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995,
Proc. SoC' Exp.. Biol. Med. 210, 162; Moodie et al,, 1993,
Science 260, 1658; Prey and Mulder, 1997, Cancer Res. 57,
628; Sivaraman et al . , 1997, «7 Clin. Invest. 99, 1478;
Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16,
5891 ,

Another aspect of the invention relates to
inhibiting ERK-2 activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a coitqposition
comprising said compound.

Another aspect of this invention relates 4:o a
method of treating or preventing an* AKT-mediated diseases
with an AKT inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.

The terms ^^AKT-mediated disease" or '^AKT-
mediated condition'' , as used herein, mean any disease or
other deleterious condition in which AKT is known to play
a role. The terms ^^AKT-mediated disease" or ^AKT.-
mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a AKT
inhibitor. AKT-mediated diseases or conditions include,
but are not limited to, proliferative di-sorders, cancer,
and neurodegenerative disorders. The association of AKT,
also known as. protein kinase B, with various diseases has
been described [Khwaja, A., Nature, pp. 33-34, 1990;
Zang, Q. Y., et al. Oncogene, 19 2000; Kazuhiko, N. , et
al. The Journal of Neuroscience , 20 2000] .

-22-

Another aspect of the invention relates to
inhibiting AKT activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a composition
5 comprising said compound. •

Another aspect of this invention relates to a
method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a

10 therapeutically effective amount of a compound, of formula
I or a pharmaceutical composition thereof.

The terms ^*Src-mediated disease^ or *Src-
mediated condition", as used herein mean any disease or
other deleterious condition in which Src is known to play

15 a role. The terms ^Src-mediated disease" or '^Src-
mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a Src
inhibitor. Such conditions include, without limitation,
hypercalcemia, osteoporosis, osteoarthritis, cancer,

20 symptomatic treatment of bone metastasis, and Paget
disease. Src protein kinase and its implication in
various diseases has been described [SoriaJio, Cell, 69,
551 (1992); Soriano et al.. Cell, 64, 693 (1991);
Takayanagi, *J. Clin. Invest., 104, 137 (1999); Boschelli,

25 Drugs of the Future 2000, 25(7), 717, (2000); Talamonti,
J. Clin. Invest., 91, 53 (1993); Lutz, Bioahem. Biaphys.
Res. 243, 503 (1998); Rosen, CT. Biol. Chem. , 261, 13754

(1986) ; Bolen, Proc . Natl. Acad. Sci. USA, 84, 2251

(1987) ; Masaki, Hepatology, 27, 1257 (1998); Biscardi,

30 Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416
(1993); Wiener, Clin. Cancer Res., 5, 2164 (1999);
Staley, Cell Growth Diff., 8, 269 (1997)].

-23-

Another aspect of the invention prelates to
inhibiting Src activity in a biological sample or a
patient, which method comprises administering to the
patient a compoiand of formula Z or a composition
5 comprising said compoiind.

Another aspect of this invention relates to a
method of treating or preventing an Lck-mediated diseases
with an Lck inhibitor, which method comprises
administering to a patient in need of such a treatment a

10 therapeutically effective amount of a compoimd of formula ^
X or a pharmaceutical composition thereof. '

The terms ^'Lck-mediated disease'' or "Lck-
mediated condition'', as used herein, mean any disease
state or other deleterious condition in which Lck is

15 known to play a role. The terras «Lck-mediated disease"
or ^Lck-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with an Lck
inhibitor. Lck-mediated diseases or conditions include,
but are not limited to, autoimmune diseases such as

20 transplant rejection, allergies, rheumatoid arthritis,
and leukemia. The association of Lck with various

diseases has been described [Molina et al.. Nature, 357, W

161 (1992)] .

Another aspect of the invention relates to
25 inhibiting Lck activity in a biological sample or a

patient, which method comprises administering to the

patient a compound of formula I or a coti^osition

comprising said compound.

The term "phainnaceutically acceptable carrier,
30 adjuvant, or vehicle" refers to a non- toxic carrier,

adjuvant, or vehicle that may be administered to a

patient, together with a corapoxmd of this invention, and

-24-

which does not destroy the pharmacological activity
thereof •

The term "patient" includes human suid
veterinary subjects.
5 The term "biological sample", as used herein,

includes, without limitation, cell cultures or extracts
thereof; preparations of an enzyme suitable for in vitro
assay; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen,

10 tears, or other body fluids or extracts thereof.

An amoimt effective to inhibit protein kinase,
for example, Aurora-2 and GSK-3, is an amoimt that causes
measurable inhibition of the kinase activity when
compared to the activity of the enzyme in the absence of

15 an inhibitor. Any method may be used to determine

inhibition, such as, for exan^le, the Biological Testing
Examples described below.

Pharmaceutically acceptable carriers that may
be used in these pharmaceutical cou^ositions are

20 generally known in the art. They include, but are not
limited to, ion exchangers, alumina, aluminum stearate,
lecithin, serum proteins, such as human serum albumin,
buffer s"ubstances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of

25 saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrol idone, cellulose-based

30 substances, polyethylene glycol, sodixim

carboxymethyl cellulose, polyacrylates , waxes,
polyethylene -polyoxypropylene -block polymers ,
polyethylene glycol and wool fat.

-25-

The compositions of the present invention may
be administered orally^ parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally
or via an implanted reservoir. The term "parenteral" as
used herein includes siibcutaixeous , intravenous,
intramuscular, intra-articular, intra -synovial ,
intrastemal, intrathecal, intrahepatic, intralesional
and intracranial injection or infusion techniques.
PrefersLbiy, the compositions are administered orally,
intraperitoneally or intravenously.

Sterile injectable forms of the con5>ositions of
this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to
techniques known in the art using suitable dispersing or
wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable
solution or suspension in a non-toxio parenterally-
acceptable diluent or solvent, for exan5>le as a solution
in 1, 3-butanediol, Among the acceptable vehicles and
solvents that may be employed are water. Ringer's
solution and isotonic sodium chloride solution. In
additionr sterile, fixed oils are conventionally employed
as a solvent or suspending medium. For this purpose, any
bland fixed oil may be employed including synthetic mono-
or di-glycerides. Fatty acids, such as oleic acid and
its glyceride derivatives are useful in the preparation
of in j eatables, as are natural pharraaceutically-
acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil
solutions or suspensions may also contain a long-chain
alcohol diluent or dispersant, such as carboxymethyl
cellulose or similar dispersing agents whic:h are commonly
used in the formulation of pharmaceutioally acceptable

-26-

dosage forms including emulsions and suspensions. Other
commonly used surfactants, such as Tweens, Spans and
other emulsifying agents or bioavailability enhancers
which are commonly used in the manufacture of
5 pharmaceutically acceptable soli-d, liquid, or other
dosage forms may also be used for the purposes of
formulation. .

The pharmaceutical compositions of this
invention may be orally administered in any orally
10 acceptable dosage form including, but not limited 'to,

capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers commonly used
include lactose and com star<:h. Iiubri<:ating agents,
such as magnesium stearate, are also typi<:ally added.
15 For oral administration in a capsule form, useful

diluents include lactose and dried cornstarch. When
aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or
20 coloring agents may also be added.

Alternatively, the pharmaceutical compositions
of this invention may be administered in the form of
suppositories for rectal administration. These can be
prepared by mixing the agent with a suitable non-
25 irritating excipient which is solid at room temperature
but liquid at rectal temperature and therefore will melt
in the rectum to release the drug.. Such materials
include cocoa butter, beeswax and polyethyleine glycols.
The pharmaceutical compositions of this
30 invention may also be administered topically, especially
when the target of treatment includes areas or organs
readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal

-27-

tract. Suitable topical formulations are readily
prepared for each of these areas or organs.

Topical application for the lower intestinal
tract can be effected in a rectal suppository formulation
5 (see above) or in a suitsible enema formulation.
Topically- transdermal patches may also be used.

For topical applications, the pharmaceutical
compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in

10 one or more carriers. Carriers for topical

administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying

15 wax and water. Alternatively, the pharmaceutical

compositions can be formulated in a suitable lotion or
cream containing the active components suspended or
dissolved in one or more pharmaceutically acceptable
carriers. Suitcible carriers include, but are not limited

2 0 to, mineral oil, sorbitan monostearate, polysorbate 60,

cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,
benzyl alcohol and water.

For ophthalmic use, the pharmaceutical
compositions may be formulated as micronized suspensions
25 in isotonic, pH adjusted sterile saline, or, preferably,
as solutions in isotonic, pH adjusted sterile saline,
either with or without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be fomulated

3 0 in an ointment such as petrolatum.

The pharmaceutical conqpositions of this
invention may also be administered by nasal aerosol or
inhalation. Such compositions are prepared according to

-28-

techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability,
5 fluorocarbons/ and/or other conventional solubilizing or
dispersing agents.

In addition to the compounds of this invention,
pharmaceutically acceptcJDle derivatives or prodrugs of
the compounds of this invention may also be employed in

10 compositions to treat or prevent the sibove.- identified
diseases or disorders.

A "pharmaceutically acceptable derivative or
prodrug" means any phaannaceutically acceptable salt,
ester, salt of an ester or other derivative of a compound

15 of this invention which, upon administration to a

recipient, is capable of providing, either directly or
indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof.
Particularly favored derivatives or prodrugs arie those

20 that increase the bioavailability of the compounds of

this invention when such compounds are administered to a
patient (e.g., by allowing an orally administered
compound to be more readily absorbed into the blood) or
which enhance delivery of the parent compound to a

25 biological compartment (e.g., the brain or lymphatic
system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the
compoimds of this invention include, without limitation,
the following derivatives of the present compounds:

30 esters, amino acid esters, phosphate esters, metal salts
sulfonate esters, carbamates, and amides.

Pharmaceutically acceptable salts of the
confounds of this invention include those derived from

-29-

pharmaceutically acceptable inorganic and organic acids
and bases. Examples of suitable acid salts include
acetate , adipat e , alginate , aspartate , benzoa te ,
benzenesulfonate, bisulfate, butyrate, citrate;
camphorate , • caraphorsul f onate / cyclopentanepropionate ,
digluconat e , dodecylsulf ate , ethahesulf onate , formate ,
fumarate, glucoheptanoate, glycerophosphate, glycolate,
hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide , hydroiodide , 2 - hydroxye thanesul f onate ,
lactate, maleate, malonate, raethanesulf onate, 2-
naphthalenesulf onate, nicotinate, nitrate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate,
succinate, sulfate, tartrate, thiocyanate, tosylate and
Tindecanoate • Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be en^loyed
in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include
alkali metal (e.g., sodium and potassium), alkaline earth
metal (e.g., magnesium), ammonium and N*(Ci-4 alkyl)4.
salts. This invention also envisions the quatemization
of any basic nitrogen- containing groups of the compoimds
disclosed herein. Water or oil -soluble or dispersible
products may be obtained by such quatemization.

The amount of the protein kinase inhibitor that
may be combined with the carrier materials to produce a
single dosage form will vary depending upon the patient
treated and the particular mode of administration.
Preferably, the compositions should be formulated so that
a dosage of between 0.01 - 100 mg/kg body weight/day of

the inhibitor can be administered to a patient receiving
these compositions.

It should also be imderstood that a specific
dosage and treatment regimen for any particular patient
5 will depend uppn a variety of -factors, including the

activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity

10 of the particular disease being treated. The amount of
the inhibitor will also depend upon the particular
compound in the composition.

Depending upon the particular protein kinase -
mediated condition to be treated or prevented, additional

15 therapeutic agents, which are normally administered to
treat or prevent that condition, may be administered
together with the inhibitors of this invention. For
example, in the treatment of cancer other
chemotherapeutic agents or other anti -proliferative

20 agents may be combined with the present compounds to

treat cancer. These agents include, without limitation,
adriamycin, dexamethasone, vincristine, cyclophosphamide,
fluorouracil, topotecan, taxol, interferons, and platinum
derivatives .

25 Other examples of agents the inhibitors of tiiis

invention may also be combined with include, without
limitation, agents for treating diabetes such as insulin
or insulin analogues, in injectable or inhalation form,
glitazones, alpha glucosidase inhibitors, biguanides,

30 insulin sensitizers, and sulfonyl ureas; anti-
inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive

-31-

agents such as cyclosporin, tacrolimus, rapamycin,
mycophenolate mofetil, interferons, corticosteroids,
cyclophophamide, azathioprine , and sulfasalazine;
neurotrophic factors such as acetylcholinesterase
5 inhibitors, MAO inhibitors, interferons, anti-
convulsants, ion channel blockers; riluzole, and anti-
parkinsonian agents; agents for treating cardiovascular
disease such as beta-blockers, ACE inhibitors, diuretics,
nitrates, calcium channel blockers, and statins; agents

10 for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti -viral agents;
agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth
factors; and agents for treating iramionodef iciency

15 disorders such as gamma globulin.

Those additional agents may be administered
separately from the protein kinase inhibitor -containing
composition, as part of a multiple dosage regimen.
AlJematively, those agents may be part of a single

20 dosage form, mixed together with the protein kinase
inhibitor of this invention in a single composition.

Compounds of this invention may exist in
alternative tautomeric forms, as in tautomers i and il
shown below: Unless otheriffise indicated, the

25 representation of either tautomer is meant to include the
other.

-32-

R'' and may be taken together to form a fused
5 ring, providing a bicyclic ring system containing Ring A.
Preferred rVR^ rings include a 5-, 6-, or 7-merabered
lansaturated or partially unsaturated ring having 0-2
heteroatoms, wherein said rVR^ ring is optionally
substituted. Examples of bicyclic systems containing
10 Ring A are shown below by compovinds I -A through I-BB,
wherein is nitrogen or C(R°) and is nitrogen or
C (H) .

I-D

Z-S

I-P

-33-

I-G

I-H

I-l

1-J

HN^
I-K

HN^
Z-L

I-M

I-N

l-O

I-p

l-Q

I-R

-34-

I-BB

Preferred bi cyclic Ring A systems include I -A,
I-B, I-C, I-E, I-F, I-I, I-J, I-K, I-P, I-Q, I-V,

and 1-U, more preferably 1-A, I-B, Z-D, I-E, I-J, I-P,
5 and 1-V, and most preferably I-A, I-B, I-D, I-E and I-J.

In the monocyclic Ring A system/ preferred R*
groups, when present, include hydrogen, alkyl- or
dialkylamino, acetamido, or a Ci-4 aliphatic group such as
methyl, ethyl, -cyclopropyl , or isopropyl. Preferred R^

10 groups, when present, include T-R^ or L-Z-r' wherein T is
a valence bond or a methylene, L is -0-, -S-, -<;(R®)20-,
-CO- or -N(R*)-, and r' is -R, -N(R*)2, or -OR. Preferred
Ry groups include 6-6 membered heteroaryl or heterocyclyl
rings, such as 2-pyridyl, 4-pyridyl, pyrrol idinyl ,

15 piperidinyl, morpholinyl, or piperazihyl ; Ci-e aliphatic,
such as methyl., ethyl, cyclopropyl, isopropyl, or

-35-

t-butyl; alkoxyalkyl amino such as methoxye thy 1 amino ; ,
alkoxyalkyl such as methoxymethyl or methoxyethyl; alkyl-
or dialkylamino such as ethylamino or dimethylamino ,\
alkyl- or dialkylaminoalkoxy such as
5 dimethylatninopropyloxy; acetamido; auid optionally

stibstituted phenyl such as phenyl or halo-s\abstituted

phenyl . .

In the bicyclic Ring A system, the ring formed
when and are taken together may be substituted or

10 unsiabstituted. Suitable substituents include -R, halo,

-0(CH2)2-4-N(R*)2/ -0{CH2)2.4-R# -OR, -NCR'*) -{CH2)2.4-N{R*)2# ®
-N(R^)-(CH2)2-4-R. -C(=0>R, -COaRi -COCOR, -NO2, -CN,
-S(0)R, -SO2R, -SR, .-N(R*)2/ -CON(R*)2/ -S02N{R*)2,
-OC{=0)R, -N{R'*)C0R, -N(R*) C02 (optionally substituted Ci-g

15 aliphatic), -N{R*)N(R*)2. -C=NN<R^)2, -C=N-OR,
-N(R^)C0N(R*)2, -N(R*)S02N(R*)2, -N(R*)S02R/ or
-0C(=0)N{R^)2/ wherein R and R^ are as defined above.
Preferred rVR^ ring siibstituents include -halo, -R, -OR,
-COR, -CC2R, -CON(R*)2/ -CN, -0<CH2)2.4-N(R*)2/ -O (CHg) 2-4-R/

20 -NO2 -N(R*)2/ -NR^COR, -NR*S02R/ -S02N(R*)2 wherein R is

hydrogen or an optionally substituted Ci-e aliphatic group.

R^ and R^' may be taken together to form a fused <Q
ring, thus providing a bicyclic ring system containing a
pyrazole ring. Preferred fused rings include benzo,

25 pyrido, pyrimido, and a partially unsaturated 6-membered
carbocyclo ring, wherein said fused ring is optionally
substituted. These are exemplified in the following
formula I compounds having a pyrazole -containing bicyclic
ring system:

-3€-

Preferred siibstitixents on tlae R^/R^' fused ring
include one or more of the following: -halo, -N(R*)2/ -C1-3
5 alkyl, -Ci-3 haloalkyl, -NO2, -O (C1-3 alkyl) , -CO2 (C1-3
alkyl) , -CN, -SO2 (Cx.3 alkyl) , -SO2NH2, -0C (0)NH2/
-NHzSOa (Ci-3 alkyl) , -NHC (O) (C1-3 alkyl ) , -C (O) NH2 , and
-CO(Ci.3 alkyl), wherein the (C1.3 alkyl) is most preferably
methyl .

10 When the pyrazole ring system is monocyclic,

preferred groups include hydrogen, Ci_4 aliphatic,
alkoxycarbonyl, (lan) siibstituted phenyl, hydroxyalkyl ,
alkoxyalkyl, aminocarbonyl , mono- or
dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl ,

15 dialkylaminoalkyl , phenylaminocarbonyl ; and (N-

heterocyclyDcarbonyl. Exan5)les of such preferred r'
substituents . include methyl, cyclc^ropyl, ethyl,
isopropyl, propyl, t -butyl, cyclopentyl, phenyl, CO2H,
CO2CH3, CH2OH, CH2OCH3, CH2CHaCH20H, CH2CH2GH2OCH3 ,

20 CH2CH2CH20CH2Ph, CHaCH2CH2NH2 , CH2Cai2CH2NHCOOC (CSIs) 3,

CONHCH(CH3)2, CONHCH2CH-CH2, CONHC3I2CH2OCH3, C01HIGH2Ph,
CONH(cyclohexyl) , CON(Et)2, CON(C3l3)CH2Ph, GOlHKn-CsHv) ,
C0N{Et)CH2CH2CH3, CONHCH2CH(CH3> 2, C»N (n-C3H7) 2, eO(3-
methoxymethylpyrrolidin-l-yl) , CONHO-tolyl) , C0NH(4-

25 tolyl) , CONHCH3, CO(morpholin-l-yl) , <:o(4-methylpiperazin-
l-yl) , CONHCH2CH2OH, CONH2, and CO{piperidin-l-yl) . A
preferred R^' group is hydrogen.

-37-

An embodiment that is particularly viseful for
treating Aurora- 2 -mediated diseases relates to compounds
o£ formula IXa:

R2

lla

or a pharmaceutically acceptable derivative or prodrug
5 thereof, wherein;

and are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having 0-3 . ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each

10 substitutable ring carbon of said fused ring formed by

and R^ is independently substituted by pxo, T-R^, or
L-Z-R^, and each stabs ti tut able ring nitrogen of said
ring formed by R^ and R^ is independently sxibstituted
by R*;

15 R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected

20 from nitrogen, oxygen or sulfur, wherein each

substitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
substituted by -R*;

25 T is a valence bond or a C1.4 alkylidene chain;

-38-

Z is a alkylidene chain;

L is -SO-, -SO2-, -N(R^)S02-, -S02N(R^)-,

-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C<0)O-,
-N(R^)CON(R^) -, -N(R^)S02N(R^) -, -N (R^)N (R^) - ,
-C(0)N(R^)-. -0C(0)N(R^)-,- -C{R^)20-/ -C<R^)2S-,
-C(R^)2SO-, -C(R^)2S02-. -C(R^)2S02N(R^) -. (R^) 2N(R^) - .
-C(R^)2N(R^)C(0)-, -C{R^)2N(R^)C(0)0-, -C(R^) =1JN(R^) - ,
.C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) SOsNCR^) - , or
-C(R^)2N(R^)CON(R^)-;

R^ and R^' are independently selected from -R, -T-W-R*, or
R^ and R^' are taken together with their intervening
atoms to fprm a fused, 5-8 membered, unsaturated or
partially iinsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein ^ach
substitutable ring carbon of said fused ring formed by
r2 and R^' is independently siibstituted by halo, 0x0,
-CN, -NO2, -R^# or -V-R^, and each siabstitutable ring
nitrogen of said ring formed by R^ and R^' is
independently substituted by R*;

r3 is selected from -R, -halo, -OR, -C(=:0)R, -CO2R,
-COCOR, -COCH2COR, -NO2/ -CN, -S(0)R, -S(0)2R/ -SR,
-N(R*)2/ -C0N(r'')2, -S02N(R'')2, -0C(=0)R, -NCR^'KOR,
-N(r'')C02(Ci-6 aliphatic) , -N(R^)N(R^) 2, -C=NN(R^)2,
-C=N-0R, -N(r'')CON(R'')2, -N(R'')S02N(R"')2, -N(R^)S02R, or

-oc{=o)n(r'')2;

each R is independently selected from hydrogen or an
optionally siibstituted group selected from Ci.e
aliphatic, Cg-io aryl, a heteroaiYl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R^ is independently selected from -R*', -GOR^,

"CO2 (optionally substituted Ci-6 aliphatic) , -C0N(r'')2/
or -SOaR^;

each is independently selected from -R^ halG, -OR,

-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SOaR, -SR,
-N(R*)2, -:C!ON(R*)2/ -S02N(R*)2, -OC{=0)R/ -N{R*)<X)R,
-N(R*)C02 (optionally substituted Ci-s aliphatic) ,
-N(R*)-N(R*)2/ -C«NN(R*)2, -C=N-OR, -N{R*) CON(R*)2/
-N(R'*)S02K(R*)2/ -N{R*)S02R, or -OC{=0)N(R*) 2;

V is -0-, -S-> -SO-, -SO2-, -N{R*)S02-, -S02N(R*)-,

. -N(R^)-, -CO-, -CO2-, -N{R*)-CO-, -N(R*)C(0)0-.,
-N(R*)CON (R®).-, -N(R*)S02N(R«)-, -N(R*)N (R*) - ,
-C(0)N(R^)-, -0C{0)N(R*) -C(R*)20-, -C(R*)2S-,
-C{R^)2S0-, -C(R^)2S02-, -C{R«)2S02N(R«)-, -C (R*) 2N (R*) - ,
-C(R^)2N(R^)C{0)-, -C(R«)2N(R«)C(0)0-, -C (R*) =NN(R*) - ,
-C(R^)=N-0-, -C(R^)2N(R«)N(R^)-, -C (R^) 2N (R^) S02N(R*) - , or
-C(R^)2N(R^) CON(R^) -;

W is -C(R*)20-, -C(R^)2S-, -C(R«)2SO-, -C(R^)2S02-,
-C(R^)2S02N(R^) -C(R^)2N(R^) -, -CO-, -CO2-,
-C(R^)OC (0) -, -C(R^)OC(0)N(R^) -, -C (R^) 2N (R^) CO- ,
-C(R^)2N(R^)C(0)0-, -C(R«)=NN(R*) -, -C(R^)=N-0-,
-C(R^)2N(R^)N(il«)-,. -C(R^)2N(R^)S02N(R^)
-C{R^)2N(R®)CON(R^) -, or -CON(R^)-;

each R* is independently selected from hydrogen or an
optionally substituted C1.4 aliphatic group, or two R®
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and

each R' is independently selected from hydrogen or an
optionally substituted Ci-s aliphatic group, or two r'
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.

Preferred rings formed by R* and R*^ include a

5-, 6-, or 7 -membered unsaturated or partially

unsaturated ring having 0-2 heteroatoms, wherein said

-40-

rVR^ ring is optionally siobstituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of f oirmula
Ila.aore shown below.

iia-J

Ila-A Ila-B lla-C

HN^ HN^ HN-^

Ila-D lla-E Ila-P

\ HN^ l*!"^

Ila-P lla-R Ila-V

-41-

HN^

Ila-W

More preferred pyrimidine ring systems of
formula Ila include Ila-A, Ila-B, Ila-D, Ila-E, Ila-J,
Ila-P, and Ila-V, most preferably Ila-A, Ila-B, Ila-D,
5 Ila-E, and lla-J.

The ring formed when R'^ and are taken
together may be substituted or unsubstituted. Suitable
substituents include -R, halo, -0(CH2)2-4-N(R^)2#
-0(CH2)2.4-Rf -OR/ -N(R*)-(CH2)2.4-N(R^)2, -N<R^) - <CH2) 2-4-R,

10 -C(=0)R, -CO2R/ -COCOR, -NO2/ -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -CON(R*)2r -S02N(R*)2. -OC(==0)R, -N(R^)COR,
-N(R*)C02 (optionally sxabstituted Ci-e aliphatic) ,
-N(R*)N(R*)2, -C=NN(R*)2, -C=N-OR, -N (R^)CON (R*) 2.
-N(R*)S02N{R*)2/ -N(R*)S02R, or -OC(=0)N(R*) 2/ wherein R and

15 R* are as defined above. Preferred R^/R^ ring

stibstituents include -halo, -R, -OR, -COR, -XSOiR,

-CON(R*)2/ -CaSr, -0(CH2)2-4-N(R*)2/>0{CH2)2.4-Rr , -NO2

-N(R*)2, -NR*COR, -NR*S02R, -S02N(R*)2 wherein R is hydrogen
or an optionally substituted Cx*s aliphatic group.

20 The R^ and R^' groups of formula Ila may toe

taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.

25 These are exemplified in the following formula lla

compounds having a pyrazole -containing bicyclic ring
system:

-42-

Preferred sxabstituents on the R^/R^' fused ring
of formula lia include one or more of the following:
-halo, -N(R*)2/ -Ci.4 alkyl, -C1.4 haloalkyl, -NO2, -OCd.*
alkyl) , -C02(Ci^4 alkyl) , -CN, -SO2 (C1-4 alkyl) , -iSOzNHz,
-0C(O)NH2, -NH2S02(Ci-4 alkyl) , -NHC(O) (C1.4 alkyl) ,
-C(0)NH2, and -CO (C1.4 alkyl) , wherein the (C1.4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (C1.4 alkyl) group is methyl or ethyl.

When the pyrazole ring system of formula Ila is
monocyclic, preferred R* groups include hydrogen or a
substituted or unsubstituted group selected from aaryl,
heteroaryl, or a C1.6 aliphatic group. Examples of such
preferred R^ groups include H, methyl, ethyl, prenyl,
cyclopropyl, ir-propyl, cyclopentyl, hydroxypropyl ,
methoxypropyl, and benzyloxypropyl ; A preferred R^' group

is hydrogen.

When Ring D of formula lla is monocyclic,

preferred Ring D groups include p^nyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula lla is laicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, . indanyl, benzimidazolyl , quinolinyl,
indolyl, isoindolyl, indolihyl, benzo [b] f uaryl ,
benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

-43-

cinnolinyl, phthalazinyl , quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl.

On Ring D of formula Ila, preferred T-R^ or
V-Z-R^ sxabstituents include -halo, -CN/ -NO2/ -N(R*)2^
5 optionally substituted Ci-e aliphatic group, -OR, -C(0)R,
-CO2R, -CONH(R*), -N(R*)COR, -N(R*)C02R, -S02N(R*)2,
-N(R*)S02R. -N(R^)COCH2N{R*)2, -N(R^) COCH2CH2N(R*) 2, and
-N(R^)COCH2CH2CH2N(R*)2r wherein R is selected from
hydrogen, Ci-e aliphatic, phenyl, a 5-6 membered

10 heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred R^ substituents include -Cl, -Br, -F, -CN,
.CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me,
-NHS02Et, -NHSO2 (n -propyl ) , -NHSO2 (isopropyl) , -NHCOEt,
-NHCOCH2NHCH3 , -NHCOCH2N (C02t-Bu) CH3, -NHCOCH2N (CHa) 2,

15 -NHCOCH2CH2N(CH3)2, -NHCOCH2CH2CH2N {CH3) 2 /

-NHCO ( cyclopropyl > , -NHCO ( i sobutyl ) , -NHCOCH2 (morpholin-4 -
yl) , -NHCOCH2CH2(morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-
4-yl) , -NHCO2 (t -butyl ) , -NH(Ci-4 aliphatic) such as -NHMe,
-N{Ci-4 aliphatic)2 such as -NMez, OH, -O (C1.4 aliphatic)

20 such as -OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and -CO2 ('Cx-4
aliphatic) .

Preferred formula Ila compounds have one or
more, and more preferably all, of the features selected
25 from the group consisting of:

(a) R"^ and R^ are taken together with their

intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
30 sulfur, or nitrogen, wherein each substitutable

ring carbon of said fused ring formed by R* and
R^ is independently substituted by 0x0, T-R^, or
L-Z-R^, and each substitutable ring nitrogen of

said ring formed by R^" and is independently
substituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(c) Ring-D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(d) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
substituted benzo ring; and

(e) R^ is selected from -R, -halo, -OR, or -N<R*)2-

More preferred compounds of formula Ila have
one or more, and more preferably all, of the features
selected from the group consisting of:

(a) R"" and R^ are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-g aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(d) R^ is selected from -R, -halo, -OR, or -N(R^)2.
wherein R is selected from hydrogen, Ci.e
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R^)- -

Even more preferred compooands of formula Ila
have one or more, and more preferably all, of the
features selected from the group consisting of:

-45-

(a) R"^ and are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;

(b) R^ is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membiered aryl or heteroaryl
ring;

(c) R^ is hydrogen or C1.4 aliphatic and R^' is
hydrogen;

(d) R^ is selected from -R, -OR, or -N(R*)2/ wherein
R is selected from hydrogen, Ci-e aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R*)2/ optionally siabstituted Ci-e aliphatic
group, -OR, -C(0)R, -CO2R, -CONH(R*) , -N<R*)COR,
-N (R^ ) CO2R , - SO2N ( R^ ) 2 / -N (R^ ) SO2R ,
-N(R^)COCH2N(R^)2, -N(R^)COCH2CH2N(R*)2. or
-N(R^)COCH2CH2CH2N(R^)2/ wherein R is selected
from hydrogen, Ci-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring,

Representative compoiands of formula Ila are
shown below in Table 1.

Table 1.

IIa-1

IIa-2

IIa-3

Me

-4€-
Me

Et

Me

HN'^ CF3

IIa-4

IIa-5

IIa-€

Me

Me

CI

Me

IIa-7

Ila-8

lla-9

Me

Me
IIa-10

Me

OH
Ila-ll

Me

F

I la- 12

Me

'^N'^S-''^*''S3Me

Me

r!NH

OC^s-O^Me

Me

OMe

IIa-13

Ila-14

IIa-15

Me

Me

Me

CI

IIa-16

Ila-17

IIa-18

-47-

IIa-19 Ila-20 lIa-21

IIa-31

IIa-32

IIa-33

-48-

IIa-43

IIa-44

IXa-4S

-49-

IIa-55 IIa-56 Ila-57

IIa-58 Ila-S9 IIa-60

-50-

/. Me

IIa-61 IIa-62 IIa-€3

Me Me ^''^

.Me

IIa-64 IIa-65 Ila-66

Me . Me . Me

oXxr'si.Me cC^^'V ^X3jar^"°

^ Me OH

IIa-67 IIa-68 IIa-69

jiir''^ -O""

Me* OMe
IIa-70 IIa-71 Ila-72

Me Me Me

HN'^^*^ HN'^^" HN'-'^N^"

NHAc

Me «vie

IIa-73 lIa-74 IIa-75

NHAc

-51-

HN

NHAc

Me Me Y

JJV" JbV" Ju^"

.... N H HN'^N H HN*^

F

lia-76 IIa-77 IIa-78

IIa-79

In another eTnbodiment/ this invention provides
a composition comprising a compound of formula Ila and a
pharmaceutically acceptable carrier.
5 Another, aspect of this invention relates to a

method of treating or preventing an Aurora -2 -mediated
disease with an Aurora -2 inhibitor, whioh method
comprises administering to a patient in need of such a
treatment a therapeutically effective amoxmt of a
10 compound of f ozmula Ila or a pharmaceutical .composition
thereof .

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method coTi5>rises administering to the patient a
15 compound of formula IXa or a coic^osition comprising ^aid
compound.

Another aspect of thi« invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK-3 inhibitor, which method con^rises
20 administering to a patient in need of such a treatment a

-52-

therapeutically effective amoiant of a compotmd of formula
Ila or a pharmaceutical con^osition thereof.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
5 blood levels of glucose in a patient in need thereof^
which method conprises administering to the patient a
therapeutically effective amount of a compound of formula
lla or a pharmaceutical composition thereof.. This method
is especially useful for diabetic patients.. Another
10 method relates to inhibiting the production of
Q hyperphosphorylated Tau protein, which is useful in

halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for

15 treating schizophrenia.

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of. formula Ila or a composition comprising said compound.

20 Another aspect of this invention relates to a

method of treating or preventing a CDK- 2 -mediated disease
with a CDK-2 inhibitor, which method comprxses
administering to a patient in need of such a treatment a
therapeutically effective amount of a compoxind of formula

25 Ila or a pharmaceutical composition thereof.

Another aspect of the invention relates to
inhibiting CDK-2 activity in a patient, which method
comprises administering to the patient a compound of
formula Ila or a composition comprising said compound.

3Q Another aspect of this invention relates to a

method of treating or preventing a Src-mediat«d disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a

-53-

therapeutically effective amount of a compound of formula
Ila or a pharmaceutical composition thereof.

Another aspect of the invention relates to
inhibiting Src activity in a patient, which method
5 comprises administering to the patient a compound of
formula Ila or a composition comprising said coirpound.

Another method relates to inhibiting Aurora-2,
GSK-3, CDK2, or Src activity in a biological sample,
which method comprises contacting the biological sample
10 with the Aurora- 2, GSK-3, CDK2, or Src inhibitor of

formula Ila, or a pharmaceutical composition thereof, in
an amount effective to inhibit Aurora-2, GSK-3, CDK2, or
Src, . .

Each of the aforementioned methods directed to
15 the inhibition of Aurora-2, GSK-3, CDK2, or Src, or the
treatment of a disease alleviated thereby, is preferably
carried out with a preferred compound of formula Ila, as
described above.

Another embodiment of this invention relates to
20 compounds of formula lib:

lib

25 or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;

and are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having 0-3 ring heteroatoms selected

-54-

from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
and is independently substituted by oxo, T-R*, or
L-Z-R^, and each substitutable ring nitrogen of said
ring formed by and R^ is independently substituted

by R*;
R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyciic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatpms selected
from nitrogen, oxygen or sulfur, wherein each
stabstitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and each
sxabstitutable ring nitrogen of Ring D is independently
substituted by -R*;

T is a valence bond or a C1.4 alkylidene chain;

Z is a Ci-4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R®)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R*)C<0)0-,
-N{R«)CON(R^)-, -N(R^)S02N(R^)-, -N (R^) N (R^) - ,
-C(0)N(R®)-, -OC(0)N(R*) -, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R^)2S02-, -C(R«)2S02N(R^)-, -C (R«) 2N (R^) - ,
-C(R*)2N{R^)C(0)-, -C(R«)2N(R^)C(0)O-, -C<R^) =NN(R*) - ,
-C{R*)=N-0-, -C(R^)2N(R«)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C (R*) 2N (R^ CON (R*) - ;

r2 and R^' are independently selected from -R, -T-W-R*, or
r2 and R^' are taken together, with their intervening
atoms to form a fused, 5-8 membered, unisaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
siibstitutable ring carbon of said fused ring formed by
R^ and R*' is independently substituted by halo, 0x0,

-55-

-CN, -NO2; -R'/ or -V-R*, and each substitutable ring
nitrogen of said ring formed by R* auid R^' is
independently siibstituted by R*;
is selected from -R, -halo, -OR, -C(ssO)R, -CO2R/
5 -COCOR, -COCH2COR, -N02,- -CN, -S(0)R, -S(0)2R/ -SR,

-N{R*)2, -CON(R')a, -S0aN(R^).2, -OC(=0)R, -N{R*')<:OR,
-N(R')C02(Ci-fi aliphatic) , -N(R*)N(R*)2, -C=NN(R*)2/
-C=N-OR/ -N(R'')C0N(R"')2, -N(r'')S02N(r')2, -N(R*)S02R, -or

-oc(=o)n(r')2;

10 each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-s
aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring liaving S-10 ring
atoms;

15 each R* is independently selected from -r"', -COR',

-CO2 (optionally substituted Ci-e aliphatic) , -C0N(R')2,
or -sb2R'';

each R^ is independently selected from -R, halo, -OR,

-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,

26 -N(R*)2, -CON(R*)2, -S02N(R*)2, -OC(=0)R, -N(R*)COR,

-N(R*) CO2 (optionally svibstituted Ci-g aliphatic) ,
-N(R*)N(R*)2, -C=NN(R*)2, rC=N-OR, -N(R'*) CON (R*) 2,
-N(R*)S02N(R*)2, -N(R*)S02R, or -OC (=0)N(R*) 2;
V is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R*)-,

25 -N(R*')-, -CO-, -CO2-, -N(R«)CO-, -N (R^) C (O) O- ,

-N(R*)CON(R*')-, -N(R«)S02N(R®) -, -N(R*)N(R'') - ,
-C(0)N(R*)-, -OC(0)N(R^)-, -C(R*)20-, -<:(R^)2S-,
-C(R«)2SO-, -C{R*)2S02-, -C(R^)2SQ2N(R*)-, -C (R^) 2N (R^) - ,
-C(R*) 2N(R*)C(0)-, -C(R*)2N(R:«)C(0) 0-, -C (R*) =NM (R*) ,

30 -C(R*)-N-0- , -C(R«)2N(R*)N(R*)-, -C (R*) 2N (R^) SO2N (R*) - , or

-C (R*) 2N (R*) CON (R*) - ;
W is -C(R*)20-, -C(R*)2S-, -C(R*)2SO-, -C(R*)2S02-,
rC{R®)2S02N(R*) -, -C(R*)2N(R«)-, -CO-, -COz- ,

-56-

10

Q

15

20

o

-C{R^)OC(0)-, -C(R^)OC(0)N(R^)-, -C (li^) 2N (R^) CO- ,
-C(R'^)2N(R^)C{0)0-, -C(R^)=NN(R^)-^ -c(r^)=n-o-,
-C (R^) 2N{R^)N(R^) - , -C (R^) 2N (R^) SO2N (R^) - ,
-C(R^)2N(R^)CGN(R*)-, or -CON(R^)-;
each R^ is independently selected from hydrogen or an
optionally substituted C1.4 aliphatic group, or two R^
groups on the same nitrogen atom are taken together
with the nitrogen atom to form, a 5-6 membered
heterocyclyl or heteroaryl ring; emd
each r'' is independently selected from hydrogen or an
optionally substituted Ci-e aliphatic group, or two r''
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
' heteroaryl ring .

Preferred rings formed by R'^ and include a
5.^ 6-, or 7 -membered unsaturated or partially
unsaturated ring having 0-2 heteroatoms, wherein said
rVR^ ring is optionally substituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula
lib are shown below.

Ilb-B

Ilb-C

Ilb-D

IZb-E

Ilb-P

-57-

Ilb-W

More preferred pyrimidine ring systems of
formula lib include llb-A, Ilb-B, Ilb-D, Ilb-B, lib- J, 0
llb-P, and Ilb-V, most preferably Ilb-A, Ilb-B, Ilb-D,
5 Ilb-B, and lib -J.

The ring formed when and R*" are taken
together may be substituted or unsxabstituted. Suitable
siibstituents include -R, halo, -O {CH2) 2-4-N (R*) 2/
-0(CH2)2-4-R, -OR, -N(R*>-(CH2)2-4-N(R*)2, -N (R*) - (CH2) 2-4-R,
10 -C{=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -CON(R*)2, -S02N(R^)2, -OC(=0)R, -N(R*)COR,
-N(R*)C02 (optionally substituted Cx-g aliphatic),
-N(R*)N(R*)2/ -C=NN(R*)2, -C=N-OR, -N(R*) CON(R*)2,
-N(R*)S02N(R*)2/ -N(R'*)S02R, or -OC (=^0) N{R*) 2, R and R* are

-58-

as defined above. Preferred R^R^ ring siibstituents
include -halo, -R, -OR, -COR, -CQ2R, -:CON(R^)2/ -CN/
-0(CH2)2-4-N(R^)2, -0(Cai2)2-4-R, / -N02-N<R*)2, -NR^GOR,
-NR*S02R, -S02N(R*)2 wherein R is hydrogen or an optionally
5 sxibstituted Ci-g aliphatic group.

The R^ and R^' groups of formula lib may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benitso, pyrido, pyrimido,
10 and a partially unsaturated €-membered carbocyclo ring.
These are exemplified in the following formula lib
.compounds having a pyrazole -containing bicyclic ring
system :

* Preferred substituents on the R^/R^' fused ring
15 of formula lib include one or more of the following:

-halo, -N(R*)2, -C1.4 alkyl, -C1-4 haloalkyl, -NO2, -0(Cx-4
alkyl) , -C02{Ci.4 alkyl) , -CN, -SO2 (C1-4 allcyl) , -SO2NH2,
-OC(0)NH2, -NH2S02(Ci.4 alkyl) , -HHC(O) (C1-4 alkyl) ,
-C(0)NH2, and -CO (C1.4 alkyl) , wherein the (C1.4 alkyl) is a
20 straight, branched, or cyclic alkyl group. Preferably,
the {Ci-4 alkyl) group is methyl or ethyl.

When the pyrazole ring system of formula lib i«
monocyclic, preferred R^ groups include hydrogen or- a
substituted or tinsubstitiited group selected from aryl,
25 heteroaryl, or a C1.6 aliphatixi: group. Examples of such

-59-

preferred groups include H, methyl/ ethyl, propyl, ,
cyclopropyl , i -propyl , cyclopejityl , hydroxypropyl ,
methoxypropyl / and benzyloxypropyl . A preferred R^' group
is hydrogen.

When Ring D of formula lib is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula lib is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
t e t rahydronaphthyl , indanyl , benzimidazolyl , quinol inyl ,
indolyl , i soindolyl , indolinyl , benzo [b] f uryl ,
benzo [b] thiophenyl , indazolyl , benzothiazolyl ,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinblinyl-

On Ring D of formula lib, preferred T-R^ or V-Z-
rS substituents include -halo, -CN, -NO2, -N(R*)2,
optionally sxibstituted Ci-6 aliphatic group, -OR, -C(0)R,
-CO2R, -C01IH(R*), -N(R*)COR, -N(R*)C02R, -S02N{R*)2,
-N(R*)S02R, -N(R^)COCH2N(R*)2/ -N (R^) COCH2CH2N(R*) 2. and
-N(R^)COCH2CH2CH2N(R*)2/ wherein R is selected from
hydrogen, Ci-e aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R^ substituents include -Cl, -Br, -F, -CN,
-CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me,
-NHS02Et , -NHSO2 (n-propyl ) , -NHSO2 ( isopropyl ) , -NHCOEt ,
-NHCOCH2NHCH3, -NHCOCH2N(C02t-Bu)CH3,. -NHCOCHaNlCHa) 2#
-NHCOCH2CH2N ( CH3 ) 2 . -NHCOCH2CH2CH2N ( CH3 ) 2 /

-NHCO ( cyclopropyl ) , -NHCO ( isobutyl ) , -NHGOCH2 (morpholin-4 -
yl ) , -NHCOCH2CH2 (morpholin-4 -yl ) , -NHCOCH2CH2CH2 (morpholin-
4-yl), -NHCO2 (t -butyl ) , -NH(Ci.4 aliphatic) such as -NHMe,'
-N(Ci.4 aliphatic) 2 such as -NMe2, OH, -0(Ci-4 aliphatic)
such as -OMe, C1.4 aliphatic such as methyl, ethyl.

-60-

cyclopropyl, isopropyl, or t -butyl/ and -C02(Ci-4
aliphatic) .

Preferred formula lib compoimds have one or
more, and more preferably all, of the features selected
from the group consisting of:

(a) R"" and are taken together with their
intervening atoms to form a fused, xinsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by R* and
R^ is independently substituted by oxo, T-R^, or
Ij-2-R^, and each substitutable ring nitrogen of
said ring formed by R* and R^ is independently
STobstituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(d) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^* are tsJcen together to form an optionally
substituted benzo ring; and

(e) R^ is selected from -R, -halo, 7OR, or -N(R*)2-

More preferred compounds of fo3naula lib have
one or more, and more preferably all, of the features
selected from the group consisting of:

' (a) R"" and R^ are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-€ membered monocyclic ring or an

-61-

8-10 metabered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-g aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(d) R^ is selected from -R, -halo, -OR, or -N(R*)2#
wherein R is selected from hydrogen, Ci-e
aliphatic, or 5-6 membered heterocyolyl, phenyl,
or 5-6 membered heteroaryl, cuid L is -0-, -S-,
or -N(R^)-.

Even more preferred corapoiinds of formula lib
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R^ and R^ are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;

(b) R^ is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring; ^

(c) R^ is hydrogen or C1-4 aliphatic and R^' is
hydrogen;

(d) R^ is selected from -R, -OR, or -N(R*)2. wherein.
R is selected from hydrogen, Ci-6 aliphatic, 5-6
membered heterocyclyl , phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R*)2. optionally substituted Ci-e aliphatic
group, -OR, -C{0)R, -CO2R, -CONH(R^) , -N{R^)COR,
-N(R*)C02R, -S02N{R*)2, -N(R*)S02R,
-N(R^)COCH2N(R^)2/ -N(R^)COCH2CH2N(R*)2. or
-N(R^)C0C3l2CH2CH2N{R*)2/ wherein R is selected
from hydrogen, C1.6 aliphatic, phenyl, a 5-6

-62-

membered heteroaryl ring, or a 5^6 metnbered
heterocyclic ring.
Representative compounds of fortaula lib are
shown below in Table 2.

Table 2.

IIb-7 IIb-8 IIb-9

In another embodiment, this invention provides
a composition comprising a compound of formula lib and a
pharmaceutically acceptable carrier.

Another aspect of this invention relates to a
method of treating or preventing an Aurora -2 -mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a

«

-63-

treatment a therapeutically effective amoiint of a
compound of formula lib or a pharmaceutical composition
thereof.

Another aspect of this invention relates to a
5 method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the pati«it a
compound of fomula lib or a composition comprising said
compound .

Another aspect of this invention relates to a

10 method of treating or preventing a GSK- 3 -mediated disease
with a GSK- 3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compoiand of formula
lib or a pharmaceutical composition thereof .

15 One aspect of this invention relates to a

method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula

20 lib or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Taii protein, which is useful in
halting or slowing the progression of Alzheimer's

25 disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for
treating schizophrenia.

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which

30 method comprises administering to the patient a compoxand
of formula lib or a composition comprising said compound.

Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method

O

-64-

comprises contacting the biological sample with the
Aurora- 2 or GSK-3 inhibitor of formula Ilb^ or a
pharmaceutical composition thereof, in an amount
effective to inhibit Axirora-2 or GSK-3.

Each of the • aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
wit-h a preferred compound of formula lib, as described
above.

Another embodiment of this invention relates to
compounds of formula lie:

lie

or a pharmaceutically acceptable derivative or prodrug

thereof, wherein;

and are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having 0-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein ^ach
siibsti tut able ring carbon of said fused ring formed by
R"" and R^ is independently substituted by oxo, T-R^, or
L-Z-R^ and each substitutable ring nitrogen of said
ring formed by R"" and R^ is independently substituted
by R\-

R^ is. T- (Ring D) ;

-65-

Ring D is a 5-7 membered tnonocyclic ring or 8-10 tnembered
bicyclic ring selected from aryl, heteroaryl^
heterocyclyl or carbocyclyl, said Ineteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
5 from nitrogen, oxygen or sulfur, wherein each

substitutable ring carbon of Ring D is independently
sxibstituted by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
substituted by -R^;
10 T is a valence bond or a C1.4 alkylidene chain;
Z is a C1.4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-/ -N(R^)S02-, -SOaNCR^)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^>C(0)0-,
.N(R^)C0N{R^)-, -N(R^)S02N{R^)-, -N (R^) N (R^) - ,

15 -C{0)N(R^)-, -0C(0)Ni[R^) -C(R^)20-, -C(R^)2S-,

-C(R^)2SO-, -C(R^)2S02-, -C(R^) 2S02N{R^) -C (R^) 2N (R^) - ,
-C(R^)2N(R^)C (0) -C{R^)2N(R^)C{0)0-, -C (R^) =NN (R^) - ,
-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) S02N(R^) - , or
-C (R^) 2N (R^) CON (R^) - ;

20 R^ and R^' are independently selected from -R, -T-W-rS or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each

25 substitutable ring carbon of said fused ring formed by

R^ and R^' is independently sxibstituted by halo, 0x0,
-CN, -NO2, -R'', or -V-R^, and each substitutable ring
nitrogen of said ring formed by R^ and R^' is
independently substituted by R*;

30 R^ is selected from -R, -halo, -OR, -C(=0)R, -CO2R,

-COCOR, -COCH2COR, -NO2/ -CN, .-S(0)R, -S(0)2R, -SR,
-N(R*)2, -C0N(R'')2, -S02N{R^)2, -OC(=0)R, -N{R^)COR,
-N(R^)C02{Ci-6 aliphatic) , -N{R*)N{R*)2, -C=NN(R*)2,

-66-

-C=N-OR, -N(R')CON(r'')2, -N(r'')S02N(R'')2, -N(R*)S02R, or
-0C{=0)N(R'')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-s
aliphatic, Cs-i© aryl, a heteroaryl ring having 5-10
ring atoms,, or a heterocyclyl ring having 5-10 ring
atoms ; ' .

each R* is independently selected from -r', -COR'',

-CO2 (optionally substituted Ci-g aliphatic) , -<:0N(r"')2»
or -SO2R';

each R^ is independently selected from -R, halo, -OR,
-C(=:0)R, -CO2R, -COCOR, -NO2, -CN, -S<0)R, -SO2R, -SR,
-N(R*)2, -CON(R*)2, -S02N(R'*>2/ -OC(=0)R, -N(R*)COR,
-N(R*)C02 (optionally substituted Ci-s aliphatic) ,
-N (R* ) N (R^ ) 2 , -C=NN (R*) 2 / -C=N-OR, -N (R*) CON (R*) ? ,
-N(R*)S02N(R*)2, -N(R*)S02R, or -OC (=0)N(R*)2;

V is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R*)-,
-N(R^)-, -CO- , -CO2-, -N(R^)CO-, -N (R*) C (O) O- ,
-N(R*)CON(R^)-, ,-N(R^)S02N(R«)-, -N (R^)N (R*) - ,
-C(0)N(R«)-, -OC(0)N(R^) -, -C(R«)20-, -C<R*)2S-,
-C(R«)2S0-, -C(R^)2S02-, -C(R«)2S02N(R*)-, -C (R«) 2N(R*) - ,
-C(R«)2N(R*)C(0)- , -C(R*)2N(R^)C(0)0-, -C<R^) =NN<R«) - ,
-C(R*)=N-0-, -C(R^)2N(R^)N(R*)-, -C (R*) 2N(R^) SO2N (R^) - ,
-C(R*)2N(R^)CON(R*) -;

W is -C(R^)20-, -C(R^)2S-, -C(R^)2SO-, -C(R^)2S02-,
-C(R*)2S02N(R^) -, -C(R^)2N(R^) -, -CO-, -CO2-,
-C(R^)OC(0)-, -C(R^)OC(0)N(R^) -, -C (R^) 2N (R^) CO-^
-C(R^)2N(R')C(0)0-, -C(R^)=NN(R*) -, -C(R^) =N-0-,
-C(R«)2N(R*)N(R*)-, -C(R^)2N(R^)S02N(R*)-,
-C(R*)2N(R*)C0N(R*)-, or -CON(R^)-;

each R* is independently selected from hydrogen or an
optionally substituted C1.4 aliphatic grovqo, or two R*
groups on the same nitrogen atom are taken together

•67-

with the. nitrogen atom to form a 5-6 membered
heterocyciyl or heteroaa^rl ring; and
each r'^ is independently selected from hydrogen or an
optionally substituted Ci-g aliphatic group ^ or two r''
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyciyl or
heteroaryl ring .

Preferred rings formed by R* and R^ include a
5-, 6-, or 7 -membered unsaturated or partially
unsaturated ring having 0-2 heteroatoms, wherein said
rVR^ ring is optionally substituted.' This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of foanmala
lie are shown below.

IIc-D IIc-E Ilc-F

Ilc-J Ilc-K

Ilc-P Ilc-R II<J-V

R'

Ilc-W

More preferred pyrimidiiie ring systems of
formula lie include Ilc-A, IXc-B, Ilc-D, Ilc-B, llc-J,
Ilc-P, and llc-v, most preferably Ilc-A, llc-B, IZc-D,

IXc-E, and IIc-J.

The ring formed when R* and R''^ of formula lie
are taken together may be s\abstituted or unsubstituted.
Suitable substituents include -R, halo, -0(CH2)2-4-N(R'*)2»
-0(CH2)2-4-R, -OR, -N(R*)-(CH2)2-4-N(R*)2, -N (R*) - «2l2) 2-4-R,
-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S{0)R, -SO2R, -SR,
-N(R*)2, -C0N(R*)2, -S02N(R*)2, -OC(=0)R, -N(R*)GOR,
-N(R*) CO2 (optionally substituted Ci-s aliphatic) ,
-N(R^)N(R*)2, -C=NN(R*)2, -C=N-OR, -N(R*) CON (R*) 2,
-N(R*).SOaN{R*)2/ -N{R*)S02R, or -OC (=0) N(R*) 2/ R and R* are
as defined above. Preferred R^/R^ ring substituents

-69-

include -halo, -R, -OR, -COR, -CO2R/ -C0N(R*)2f -CN,
-0{Cai2)2.4-N{R*)2, -0(CH2)2.4-R, / -NO2 -N(R*)2, -NR^COR,
-NR^S02R/ -S02N{R*)2 wherein R is hydrogen or an optionally
sxabstituted Ci^e aliphatic group*
5 The R^ and R^' groups of formula lie may be

taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
10 These are exemplified in the following formula lie

compoiands having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R^/R^' fused ring
of formula lie include one or more of the following:

15 -halo, -N(R^)2/ -C1-4 alkyl, -C1.4 haloalkyl, -NO2, -0(Ci-4
alkyl) , -C02(Ci-4 alkyl) , -CN, -SO2 (C1-4 alkyl) , -SO2NH2.
-0C(0)NH2/ -NH2SO2 (C1.4 alkyl) , -NHC(O) (C1.4 alkyl) ,
tC(0)NH2, and -CO (C1.4 alkyl) , wherein the (C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,

20 the (C1.4 alkyl) group is methyl.

When the pyrazole ring system of formula lie is
monocyclic, preferred R^ groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a Ci-g aliphatic group. Exan5>les of such

25 preferred R^ groups include H> methyl, ethyl, propyl, ,

9

( l

"70-

cyclopropyl, i -propyl, cyclopentyl, hydroxypropyl ,
methoxypropyl/ and benzyloxypropyl • A preferred R^' group

is hydrogen.

When Ring D of formula lie is monocyclic,
5 preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula lie is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl.,

10 indolyl, isoindolyl, indolinyl, benzo [b] f uryl ,
benzb[b] thiophenyl, indazqlyl, benzothiazolyl ,
cinnolinyl, phthalazinyl/ quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl aiid isoquinolinyl.

On Ring D of formula lie, preferred T-R^ or

15 V-Z-R^ substituents include -halo, -CN, -N02f -N(R*)2/

optionally substituted Ci-6 aliphatic group, -OR, -C{0)R,
-CO2R, -CONH(R*), -N(R*)C0R, -N(R*)C02R, -S02N(R*)2/
-N(R*)S02R, -N(R*^)COCH2N(R*)2, -N(R^)<:OCH2C3l2N(R*) 2, and
-N(R^)C0CH2CH2CH2N(R^)2i wherein R is selected from

20 hydrogen, Ci-e aliphatic, phenyl, a 5-6 membered

heteroaryl ring, or a 5-6 membered heterocyclic ring-
More preferred substituents include -CI, -Br, -F, -CW,
-CF3, -COOH, -CONHMe, -CONHEt, -ISIH2, -NHAc, -NHS02Me,
-NHSOaEt, -NHS02(n-propyl) , -NHSO2 (isopropyl) , -NHCOEt,

25 -NHCOCH2NHCH3/ -NHC0CH2N(CO2t-Bu)CH3, -NHCOCH2N (CH3) 2/
-NHCOCH2CH2N ( CH3 ) 2 r -NHCOCH2CH2CH2N ( CH3 ) 2 /

-NHCO (cyclopropyl) , -NHCO (isobutyl) , -NHCOCH2<morpholin-4-
yl) , -NHCOCH2CH2(morpholin-4-yl) , -NHCOCH2CH2CH2 {mozpholin-
4-yl), -NHC02(t-butyl) , -NH(Ci.4 aliphatic) such as -NHMe,
30 -N{Ci.4 aliphatic) 2 such as -NMez, OH, -0{Ci-4 aliphatic)
such as -OMe, C1-.4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t -butyl, and -C02<Ci.4.
aliphatic) .

-71-

Pref erred formula lie compoiinds have one or
more, and more preferably all, of the features selected
from the group consisting of:

(a) and are taken together with their
intervening -atoms to form a fused, unsaturated
or partially unsaturated^ 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by R* and
Ry is independently substituted by oxo, T-R^, or
L-Z-R^, and each substitutable ring nitrogen of
said ring formed by R* and R^ is independently
sxabstituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(d) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
r2' are taken together to form an optionially
substituted benzo ring; and

(e) R^ is selected from -R, -halo, -OR, or -N(R*)2.

More pref erxed compounds of formula lie have
one or more, and more preferably all, of the features
selected from the group consisting of:

(a) and R^ are taken together to fo3nn a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

-72-

(c) is -R and R^' is hydrcjgen, wherein R is
selected from hydrogen, Ci-g aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 metnbered
heterocyclic ring; and

(d) is -selected from -R, -halo, -OR, or -N(R*)2/
wherein R is selected from hydrogen, Ci-s
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R*)-.

Even more preferred compounds of formula lie
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R* and R^ are taken together to form a benzo,
pyrido, piperidino, or cyclohexo- ring;

(b) R* is T-Ring D, wherein T is a valence bond and
Ring P is a 5-6 membered aryl or heteroaryl
ring;

(c) R^ is hydrogen or C1-4 aliphatic and R^ is
hydrogen;

(d) R^ is selected from -R, -OR, or -N(R*)2, wherein
R is selected from hydrogen, Ci-s aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R^)2, optionally substituted Ci-e aliphatic
group, -OR, -C(0)R, -CO^R, -CONH(R*) , -N<R*)<20R,
-N(R*)C02R, -S02N(R'*>2, -N(R'*)S02R,
-N(R«)C0CH2N(R*)2/ -N(R^)GOCH2CH2N(R*)2, or

-N (R^) COCH2CH2CH2N (R* ) 2 , wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

-73-

Preferred compoxinds of formula lie include
compounds of formula lie' :

r2

lie'

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;

R*" and are taken together with their intervening atoms
to form a fused benzo ring, wherein each substitutable
ring carbon of said fused ring formed by R* and R^ is
independently stibstituted by T-R^, or L-Z-R^;

R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterbcyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
substituted by -R^;

T is a valence bond or a Cx-4 alkylidene chain;

Z is a Ci-4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -SOzNCR^)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N<R^)C(0)0-,
.N.(R^)C0N(R^)-, -N (R^)S02N(R^)-, -N (R^) N (R^) - ,
-C (O) N (R^) - -OC (0> N (R^) - , -C (R^) 2O- , . -C (R^) 2S- ,

-74-

-C(R«)2SO-, -C(R«)2S02-, -C(R^)2S02N(R^) -C (R^) 2N (R^) - ,
-C{R«)2N(R*)C(0)-, -C(R«)2N(R^)C(0)0-, -C (R^) =NN (R^) - ,
-C(R«)=N-0-, -C{R^)2N(R*)N(R*)-, -C (R*) 2N (R*) SO2N (R^) - , or
-C (R* ) 2N (R* ) CON (R* ) - ;

R* and R^' are independently selected from -R, -T-W-R*, or
R^ and R^' are taJcen together with their intervening
atoms to form a fused, 5-8 membered, unsatiirated or
partially imsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
r2 and R=' is independently stabstituted by halo, 0x0,
-CN, -NO2, -R'/ of -V-R*, and each siibstitutable ring
nitrogen of said ring formed by R^ and R^' is
independently siibstituted by R*;

R^ is selected from -R, -halo, -OR, -C(=6)R, -CO2R,
-COCOR> -COCH2COR, -NO2, -CN, -S{0)R, -S(0)2R, "SR,
-N(R*)2, -C0N(R')2, -S02N(R'')2, -0C(=0)R, -N(R')C0R,
-N(r'')C02(Ci.6 aliphatic) , -N(R*)N(R*)2/ -C=NN(R*)a,
-C=N-0R, -NCR') CON (r') 2, -N(R'')S02N(R')2, -N(R*)S02R, or

. -oc(=o)n(r'')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-e
aliphatic, Cg-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ;

each R* is independently selected from -R"', -COR',

-CO2 (optionally substituted Ci-6 aliphatic) , -C0N{r')2/

or -SOaR^;

each R^ is independently selected from -R, halo, -OR,
-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -C0N(R*)2, -S02N{R*)2, -OC(=0)R, -N(R*)COR,
-N(R*)C02 (optionally substituted Ci-« aliphatic) ,

-75-

-N(R*)N(R'')2, -C=NN(R*)2, -C=N-OR, -N (R^) CON (R*) 2,
-N(R*)Sb2N(R*)2, -N(R*)S02R, or -OC (=0)N(R*) 2;
V is -0-, rS-, -SO-, -SO2-, -N(R®)S02-, -S02N(R^)-,
-N(R*)-, -CO-, -CO2-, -N{R*)CO-, -N(R*)C(0)0-,
5 -N (R*) CON (R*) - , • -N (R*) SO2N (R*) - , -N (R*) N (R*) - /

-C(0)N(R*)-, -OC(0)N(R*)-, -C(R^)20-, -C(R*)2S-,
-C (R*) 2SO- , . -C (R*) 2SO2- , -C (R^) 2SO2N (R*) - , -C (R*) 2N (R*) - ,
-C(R*) 2N(R^)C (0)-, -C(R«)2N(R*)C(0)0-, -C (R*) =NN(R*) - ,
-C(R«)=N-0-, -C(R<')2N (R*)N{R*)-, -C (R«) 2N (R*) S02N(R«) - , or
10 -C(R*)2N{R*)CON(R*)-;

W is -C{R*)20-, -C(R*)2S-, -C(R«)2SO-, -C (R*) 2SO2- ,
-C(R*)2S02N{R*)-, -C(R*)2N(R*)-, -CO-, -CO2-,
-C(R*)OC(0)-, -C(R*)OC(0)N(R*) -, -C (R*)2N (R:*)CO-,
-C{R^)2N(R*)C(0)0-, -C(R*)=NN(R«)-, -C(R*)=N-0-,
15 -C(R*)2N(R^)N(R®) -, -C(R'')2N(R*)SOaN{R«)-,

-C(R^)2N(R^)CON(R^) -, or -CaN(R*)-;
each R^ is independently selected from hydrogen or an
optionally substituted C1.4 aliphatic group, or two R*
groups on the same nitrogen atom are teJcen together
20 with the nitrogen atom to form a 5-6 membered

heterocyclyl or heteroaryl ring; and
each R*' is independently selected from hydrogen or an
optionally sijbstituted Ci,6 aliphatic group, or two r'
on the same nitrogen are taken together with the
25 nitrogen to form a 5-8 membered heterocyclyl or

heteroaryl ring.

The ring foanned when R* and R^ of f cannula lie'
are taken together may be substituted or unsxabstituted.
Suitable substituents include -R, halo, -0(CH2)2-4-N(R*)2,
30 -0(CH2)2-4-R, -OR, .-N(R*)-{CH2)2-4-N(R*)a> -N (R*) - (CH2) 2-4-R,
-C{=0)R, -CO2R, -COCOR, -NOa, -CN, -S{0)R, -SO2R, -SR,
-N(R*)2, -C0N(R*)2, -S02N(R*)2, -OC(=0)R, -N(R*)COR,
-N(R*)C02 (optionally substituted Ci-s aliphatic).

<

-76-

10

15

-N(R*)N(R'*)2/ -C=NN{R*)2, -C=N-OR, -N (R*) CON (R*) 2/
-N(R*)S02N(R*)2. -N(R*)S02R, or -OC (=0) N (R*) 2/ wherein R and
R* are as defined above. Preferred R*/R^ ring
sTjbstituents include -halo, -R, -OR, -COR, -CO2R,
.-CON(R*)2, -CN, -0(CH2)2-4-N(R*>2/ -O (CH2) 2-4-R. / "NOa
-N(R*)a» -NR*COR, -NR^SOaR, -S02N(R*)2/ wherein R is
hydrogen or an optionally substituted Cx-e aliphatic group.

The R^ and R^' groups of formula IIC may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclb ring.
These are exemplified in the following formula lie'
compounds having a pyrazole- containing bicyclic ring
system:

H

»N "i-C^

and

Preferred substituents on the R^/R^' fused ring
20 of formula IIC include one or more of the following:
-halo, -N{R*)2, -Ci-4 alkyl, -C1.4 haloalkyl, -NO2, -0(Ci-4
alkyl), -C02(Ci_4 alkyl) , -CN, -SO2 (C1.4 alkyl) , -SO2NH2,
-0C(0)NH2, -NH2S02(Ci-4 alkyl) , -NHC(O) (C1.4 alkyl) ,
-C(0)KH2, and -C0{Ci-4 alkyl) , wherein the (C1-4 alkyl) is a
25 straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl.

When the pyrazole ring system of formula lie'
is monocyclic, preferred R^ groups include hydrogen or a

-77-

substituted or unsubstituted group selected from aryl,
heteroaryl , or a Ci-e aliphatic groijp . Exan?)les of such
preferred groups include H, methyl, ethyl, prqpyl, ,
cycloprqpyl, i -propyl, cyclopentyl, hydroxypropyl ,
5 methoxypropyl, . and-benzyloxypr<^yl. A preferr^ed R^' group

is hydrogen.

When Ring D of formula lie' is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

10 When Ring D of formula lie' is bicyclic, _

preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl , indanyl, benzimidazolyl , quinolinyl,
indolyl,. isoindolyl, indolinyl, benzo [b] f uryl ,
benzo [b] thiophenyl , indazolyl, benzothiazolyl ,

15 cinnolinyl, phthalazinyl , quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl .

On Ring D of formula IIC , preferred T-R' or '
V-Z-R^ substituents include -halo, -CN, -NO2, -N(R*)2,
optionally substituted Ci-e aliphatic group, -OR, -C(0)R,

20 -CO2R, -CONH(R*), -N(R*)COR, -N(R*)C02R, -S02N(R*)2,

-N(R*)S02R, -N(R^)COCH2N(R*)2, -N (R*) COCH2CH2N<R*) 2, and ^
-N(R*)COCH2CH2CH2N(R'*)2, wherein R is selected from. ^
hydrogen, Ci-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.

25 More preferred R^ substituents include -Cl, -Br, -F, -CN,
-CF3, -COOH, -CONHMet -CONHEt, -NH2, -NHAc, -NHS02Me,
-NHSOzEt, -NHS02(n-propyl) , -NHS02(isopropyl) , -NHCOEt,
-NHCOCHaNHCaia, -NHCOCH2N (C02t-Bu) CH3 , -NHCOCH2N (CH3) 2,
-NHCOCH2CH2N(CH3)2, -NHC0CH2CH2CH2N{CH3) 2/

30 -NHCOCcyclopropyl) , -NHCO (isobutyl) , -NHCOCH2 (morpholin-4-
yl) , -NHC0CH2CH2(morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-
4-yl) , -NHCO2 (t -butyl ) , -NH(Ci-4 aliphatic) such as -MMe,
-N(Ci.4 aliphatic) 2 such as .-NMea, OH, -0(Ci.4 aliphatic)

-78-

such as -OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl; isopropyl, or t -butyl, and -C02(Ci.4
aliphatic) .

Preferred formula lie' compounds have one or
more, and more preferably all, of the featoires selected
from the group consisting of:

(a) is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(b) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
substituted benzo ring; and

(d) R^ is selected from -R, -halo, -OR, or -N<R*)2-

More preferred compounds of formula IIC have
one or more, and more preferably all, of the features
selected from the group consisting of :

fa) is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(b) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-^ aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(c) R^ is selected from -R, -halo, -OR, or -N(R^)2/
wherein R is selected from hydrogen, Cx.e
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or «N(R^)-.

-79-

Even more preferred compounds of formula He'

have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

(b) R^ is hydrogen or C1-4 aliphatic and R^' is
hydrogen;

(c) R^ is selected from -R, -OR, or -N(R*)2/ wherein

membered heterocyclyl/ phenyl, or 5-6 membered

substituents selected from -halo, -CN, -NO2/
-N{R^)2/ optionally substituted Ci-e aliphatic
group, -OR, -C(0)R, -CO2R, -CONH{R^) , -N(R^)COR,
-N(R^)C02R, -S02N{R*)2, -N(R^)S02Rr
-N(R^)COCH2N(R*)2, •N(R^)COCH2CH2N(R*)2. or
-N(R^)COCH2CH2CH2N{R^)2, wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
Other preferred compounds of formula lie

R is selected from hydrogen, Ci-6 aliphatic, 5-6

heteroaryl, and L is -0-, -S-, or -NH-; and
(d) Ring D is substituted by up to .three

include compoiinds of formula lie":

r2

H

He"

-80-

or a pharmaceutically acceptable derivative or prodrug
thereof , wherein;

R* and are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
-5-7 membered ring having 0-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each
sxibstitutable ring carbon of said fused ring formed by
R* and ny is optionally substituted by oxo, T-R*, or L-
Z-R^, and each substitutable ring nitrogen of said ring
formed by R* and R^ is optionally sxabstituted by R*;
provided that said fused ring formed by R* and R*" is
other than benzo;

R^ is T- (Ring D) ,-

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur,, wherein each
substitutable ring carbon of Ring D is independently
siibstituted by oxo, T-R^, or V-Z-R^, and each
sxabstitutable ring nitrogen of Ring D is independently
substituted by -R*;

T is a valence bond or a 01-4 alkylidene chain;

Z is a Ci-4 alkylidene chain;

I. is -0-, -S-, -SO-, -SO2-, -N(R*)S02-, -SOzNCR*)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C(0)0-,
-N(R^)CON.(R^)-, -N{R^)S02N(R*) -, -N (R^)N (R*) - ,
-C(0)N(R^)-, -OC(0)N(R^) -, -C(R*)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R*)2S02-, -C(R^)2S02N(R^)-, -C (R^) 2N (R*) - ,
-C(R^)2N (R^)C(0)-, -C(R^) 2N(R^)C(0)0-, -C (R^) =NN (R*) - ,
-C(R«)=N-0-, -C(R^)2N{R«)N(R^)-, -C (R^) 2N(R^) SO2N (R*) - , or
-C(R«)2N(R*)C0N(R*)-;

-81-

r2 and R*' are independently selected from -R, -T-W-R^, or
r2. and R^' are 'taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsatxirated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R* and R*' is independently substituted by halo, oxo,
-CN, -NO2, -R'» or -V-R*, and each siabstitutable ring,
nitrogen of said ring formed by R^ amd R*' is
independently substituted by R*;

R^ is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COGH2COR, -NO2, -CN, -S(0)R, -S(0)2R, "SR,
-N(R*)2, -CON(r')2, -S02N(R'')2, -oc{=o)r, -n(r7)gor,
-N(R')C02(Ci.6 aliphatic) , -N(R*)N(R*) 2, -C=NN(R*)2,
-C-=N-OR, -N(R^)C0N(R')2, -N(R')S02N(R')2/ -N(R*)S02R, or

-oc(=6)n(r')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-e
aliphatic, Ce-ib aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ;

each R* is independently selected from -r', -COR',

-CO2 (optionally substituted Ci.« aliphatic) , -C0N(R^)2,
or -SO2R';

each R^ is independently selected from -R, halo, -OR,
-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S<0)R, -SO2R, -SR,
-N(R*)2/ -CON(R*)2, -S02N(R*)2, -OC(=0)R, -N(R*)COR,
-N{R*)C02 (optionally s-ubstituted Ci_6 aliphatic) ,
-N(R*)N(R*)2, -C=NN(rM2/ -C=N-0R, -N (R*) CON (R*) 2,
-N(R*)S02N(R*)2, -N(R*)S02R, or -OC (=0)N(R*)2;

V is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R^)-,
-NCR*)-, -CO-, -CO2-, -N(R«)CO-, -N(R«)C(O)0-,
-N(R*)C0N(R«)-, -N(R*) S02N(R«)-, -N(R«)N(R^) - ,

-82-

-C(0)N(R*) -, -OC(0)N(R^) -C{R*)20-, -C {R^)2S-,
-C(R*)2S0- , -C(R^)2S02-, -C(R^)2S02N(R^)-, -C (R*) 2N (R«) -
-C(R^)2N(R*)C (0) -C(R^)2N(R^) C(0)0-, -C (R«) =NN (R^) - ,
-C{R*)=N-0-, -C(R«)2N(R«)N(R*)-, -C (R*) 2N (R^) SOaN<R^) - , or
5 -C(R^)2N(R*)CON(R*)-; -

W is -C(R*)20-, -C(R*)2S-, -C(R^)2SO-, -C(R*)2S02-,
-C(R*)2S02N(R*)-, -C{R*)2N(R*)-/ -CO-, -CO2-,
-C(R*)OC(0)-, -C(R«)OC(0)N(R*)-, -C (R*) 2N (R*) CO- ,
-C(R*)2N(R*)C(0)0-, -C{R*)-NN(R«)-, -C(R*)=N-0-,
10 -C{R*)2N(R*)N(R*)-, -C(R*)2N(R*)S02N(R*)-,

O -C(R®)2N{R*)CON(R*)-, or -CON(R*)-;

each is independently selected from hycUrogen or an
optionally substituted Cx-4 aliphatic group, or two R*
groups on the same nitrogen atom are taken together
15 with the nitrogen atom to form a 5-6 membered

heterocyclyl or heteroaryl ring; and
each r' is independently selected from hydrogen or an
optionally substituted Ci-s aliphatic groi:^, or two r'
on the sane nitrogen are taken together with the
20 nitrogen to form a 5-8 membered heterocyclyl or

heteroaryl ring.

f ) Preferred rings formed by R* and R^ of formula

lie" include a 5-, 6-, or 7 -membered vmsaturated or
partially unsaturated ring having 1-2 heteroatoms, or a
25 partially unsaturated carbocyclo ring, wherein said ^/R^
ring is optionally substituted. This provides a bicyclic
ring system containing a pyrimidine ring. Exau^les of
preferred pyrimidine ring systems of formula 11c" are
shown below.

-83-

HN^ HN-^ HN-^

1IC"-D

IIC"-B

IlC"-C

IIC"-B

IIC"-P

HN^

IIC"-K

IIC"-L

c6

IlC'«-P

CcX f*iv pi'r

Ilc"-R Iic"-V llc"-W

More preferred pyrimidine ring systems of
formula lie" include IIc"-B, IXc-D, IIc-E, Ilc-J, Ilc-P,
and IIc-V, most preferably IIc-B, XIc-D, XXc-E, and XIc-

The ring formed when and of formula IXc"
are taken together may be siabstituted or unsubstituted.
Suitable substituents include -R, halo, -0(CH2)2-4-N(R*)2/
-0(CH2)2-4-R, -OR, -N(R*)-(CH2)2-4-N(R*)a, -N (R*) - (CHa) a-4-R/

-84-

-C(=0)R. -CO2R, -COCOR, 'CN, -S(0)R, -SO2R, ~SR,

-N(R*)2, -C0N(R^)2, -S02N(R^)2, -OC{«0)R, -N(R*)COR,
-N{R*)C02 (pptibnally substituted Ci-6 aliphatic),
-N(R*)N(R*)2, -C=NN(R*)2, -C=N-OR, -N(R^) CON(R*) 2,
5 -N(R*)S02N(R*) 2, -N(R^)S02R, or -OC (=0)N(R*) 2/ wherein R and
R^ are as defined above. Preferred rVR^ ring
substituents include -halo, -R, -OR, -COR, -CO2R,
-CON(R*)2, -CN, -0(CH2)2.4-N{R*)2. -O {CH2) 2.4-R/ . -NO2
-N(R*)2/ -NR^COR, -NR*S02R, -S02N(R*)2 wherein R is hydrogen
10 or an optionally siibstituted Ci-e aliphatic group.
\, 5 The R^ and R^' groups of formula lie" may be

taken together to form a fused ring, thus providing a
bi cyclic ring system containing a pyrazole ring.
Preferred fused rings include benzq, pyrido, pyrimido,
15 and a partially unsaturated e-membered -carbocyclo ring-
These are exemplified in the following formula lie"
compounds having a pyrazole -containing bicyclic ring
system:

Preferred substituents on the R^/R^' fused ring
20 of formula lie" include one or more of the following:

-halo, -N(R^)2/ -C1.4 alkyl, -C1.4 haloalkyl, -NO2, -0(Ci-4
alkyl), -C02(Ci.4 alkyl) , -CN, -SO2 (C1.4 alkyl) , -S02NH2>
-OC(0)NH2, -NH2S02(Ci.4 alkyl) , -NHC(O) (C1-4 alkyl) ,
-C(0)NH2, and -CO (Cx.4 alkyl) , wherein the (C1-4 alkyl) is a

J

-85-

straight, branched, or cyclic allcyl group* Preferably,
the (C1.4 alkyl) group is methyl.

When the pyrazole ring system of formula lie"
is monocyclic, preferred groups include hydrogen or a
5 sxabstituted or unsiabstituted group selected from aryl,
heteroaryl, or a Ci.€ aliphatic group. Examples of such
preferred groups include methyl, ethyl, propyl, ,
cyclopropyl , i -propyl , cyclopentyl , hydroxypropyl ,
methoxypropyl , and benzyloxypropyl . A preferred R^' group

10 is hydrogen.

When Ring D of formula He" is monocyclic, ©

preferred Ring D groups include phenyl, pyridyl,

pyridazinyl, pyrimidinyl, and pyrazinyl-

When Ring D of formula lie" is bicyclic,
15 preferred bicyclic Ring D groups include naphthyl,

tetrahydronaphthyl , indanyl, benzimidazolyl , quinolinyl,

indolyl, isoindolyl, indolinyl, benzo [b] f uryl ,

benzo[b] thiophenyl, indazplyl, benzothiazplyl ,

cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl>
20 1, 8-naphthyridinyl and isoquinolinyl.

On Ring D of formula lie", preferred T-R^ or

V-Z-R^ substituents include -halo, -CN, -NO2, -N(R )2/ . Kj

optionally siibstituted Ci-e aliphatic group, -OR, -C(0)R,

-CO2R, -CONH(R*), -N(R*)COR, -N(R*)C02R, -S02N(R*)2/
25 -N(R'')S02R, -N(R^)COCH2N(R*)2, -N (R^) COCH2CH2N(R*) 2, and

-N(R^)C0CH2CH2CH2N(R*)2, wherein R is selected from

hydrogen, Ci-g aliphatic, phenyl, a 5-6 metnbered

heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred R* substituents include -Cl, -Br, -F, -CN,
30 -CP3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me,

-MHS02Et, -MHS02(n-propyl) , -NHSO2 (isopropyl) , -NHCOEt,

-NHCOCH2NHCH3, -NHCOCH2N(C02t-Bu)CH3, -NHCOCH2N (CH3) 2r

-NHCOCH2CH2N (013)2, -NHCOCH2CH2CH2N(CH3)2/

-86-

-NHCO { cyclopropyl ) , -NHCO ( i sobutyl ) , -NHCOCH2 (morpholin-4 -
yl) , -NHCOCH2CH2 {morpholin-4 -yl) , -NHCOCH2CH2CH2 (morpholin-
4-yl), -NHC02(t-butyl) , -NH(Ci.4 aliphatic) such as -NHMe,
-N(Ci-4 aliphatic)2 such as -NMe2/ OH, -0(Ci.4 aliphatic)
5 such as -OMe, Ci-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t- butyl,, and -C02(Ci-4
aliphatic) .

Preferred formula lie" compounds have one or
more, and more preferably all, of the features selected
10 from the group consisting of:
( ') (a) R'^ and are taken together with their

intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 1-2 heteroatoms selected from oxygen,
15 sulfur, or nitrogen, or a part:ially unsaturated

6 -membered carbocyclo ring, wherein each
substitutable ring carbon of said fused ring
formed by R* and is independently substituted
by 0x0, T-R^, or L-Z-R^, and ea<di substi^iutable
20 ring nitrogen of said ring formed by R^ and R^ is

independently substituted by R"*;
) (b) R^ is T- (Ring D) , wherein T is a valence bond or

a methylene unit, and Ring D is a 5-7 membered
monocyclic or an 8-10 membered bicyclic aryl or
25 heteroaryl ring;

(c) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
stibstituted benzb ring; and

(d) R^ is selected from -R, -halo, -OR, or -NCR'*) 2.
30 More preferred compounds of formula lie" have

one or more, and more preferably all, of the features
selected from the group consisting of:

-87-

(a) R"^ and are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring, wherein
each svibstitutable ring carbon of said fused
ring formed by R"" and is independently
siabstituted by oxo, T-R^, or L-Z-R^, and each
Slabs ti tut able ring nitrogen of said ring formed
by R^ and R^ is independently substituted by R^;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 metnbered monocyclic ring or an
8-10 membered bicyclic ring selected from an.
aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Cx-e aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a. 5-6 membered
heterocyclic ring; and

(d) R^ is selected from -R, -halo, -OR, or -N(R*)2/
wherein R is selected from hydrogen, Ci.e
aliphatic, or 5-6 membered heterocyclyl,. phenyl,
or 5-6 membered heteroaryl, and L is -0-,

or -N{R*)-.

Even more preferred compounds of formula lie"
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R"" and R^ are taken together to form a pyrido,
piperidino, or cyclohexo ring, wherein each
substitutable ring carbon of said fused ring
formed by R^ and R^ is independently substituted
by oxo, T-R^, or L-Z-R^, and each substitutable
ring nitrogen of said ring formed by R* and is
independently substituted by R^;

-88-

(b) is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

(c) R^ is hydrogen or C1.4 aliphatic and R^' is
hydrogen; •

(d) R^ is selected from -R, -OR, or -N(R^)2, wherein
R is selected from hydrogen, Ci-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
hetjBroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R*)2/ optibnally substituted Cx-e aliphatic
group, -OR, -C(0)R, -CO2R, -CONH{R*) , -N(R^)COR,
-N(R*)C02R, -S02N(R*)2, -N{R^)S02R,
-N{R^)COCH2N(R*)2, -N(R^)COCH2CH2N(R^)2. or
-N(R^)COCH2CH2CH2N(R'*)2, wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

Representative compovinds of formula lie are
shown below in Table 3 •

Table 3.

OH

IIc-1 IIc-2 IIc-3

H

IIC-4

Me
HN^

IIC-S

Me
HN N

H

IIc-7

Me
IIC-8

Me .
Ilc-lp

Me
H

IIc-11

fvie

Me
C5H

IIC-13

IIC-14

Me

H

IIc-6

Me

H

IlC-12

Me

• H

IIc-16

IIc-17

IK3-18

-90-

lIC-19 IIC-20 IIc-21

IIc-28

IIC-29

IIC-30

-51-

IIC-34 IIc-35 IIC-36

lIC-37 IIC-38- IIC-39

IIC-40

IIC-41

IIC-42

IIC-S2 IIC-S3 IIC-54

-93-

-94-

H

IIC-70

■ IlC-73

H CF3
IIC-76

Me

H

IIc-71 IIC-72

IIc-79

IIC-80

IIc-81

IIC-88 IIC-89 IIC-90

In another ettibodiment , this invention provides
a coic5)osition comprising a conqpoiind of formula lie, IIC ,
or lie", and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a
method of treating or preventing an Aurora -2 -mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula lie, lie', or lie", or a
pharmaceutical composition thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient.

-96-

which method comprises administering to the patient a
compoxand of formula lie, IIC , or lie", or a composition
con^ri sing said compoiind.

Another aspect of this invention relates to a
5 method of treating or preventing a GSK- 3 -mediated disease
with a QSK-3 inhibitor, which method compri-ses
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
lie, lie', or lie", or a pharmaceutical composition
10 thereof.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a

15 therapeutically effective amoiant of a con?>ound of formula
He, He', or lie", or a pharmaceutical composition
thereof. This method is especially useful for diabetic
patients. Another method relates to inhibiting the
production of hyperphosphorylated Tau protein, which is

20 useful in halting or slowing the progression of .
Alzheimer's disease. Another method relates to
inhibiting the phosphorylation of p-catenin, which is
useful for treating schizophrenia.

Another aspect of this invention relates to a

25 method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula lie, lie', or lie", or a composition
comprising said compound.

Another aspect of this invention relates to a

30 method of treating or preventing a Src-raediated disease
with a Src inhibitor, which method conrprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of foinnula

• 97-

IIc, lie, or lie", or a pharmaceutical composition
thereof.

Another aspect of the invention relates to
inhibiting Src activity in a patient, which method
comprises administering to the patient a confound of
formula IXc, IIC , or lie", or a composition comprising
said compound*

Another aspect of this invention relates to a
method of treating or preventing an ERK- 2 -mediated
diseases with an ERK-2 inhibitor, which method con^rises
administering to a patient in need of such a treatment a
therapeutically effective amount of. a compound of formula
lie, lie', or lie", or a pharmaceutical composition
thereof.

Another aspect of the invention relates to
inhibiting ERK-2 activity in a patient, which method
comprises administering to the patient a compound of
formula lie, lie', or lie", or a con?)osition comprising
said compound.

Another aspect of this invention relates to a
method of treating or preventing an AKT-mediated diseases
with an AKT inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compo\ind of formula
lie, lie', or lie", or a pharmaceutical composition
thereof.

Another aspect of the invention relates to
inhibiting AKT activity in a patient, which method
comprises administering to the patient a compound of
formula lie, lie', or lie", or a composition comprising
said compound •

Another method relates to inhibiting Aurora-2,.
GSK-3, Src, ERK-2, or AKT activity in a biological

-98-

sample, which method comprises contacting the biological
sample with the Aurora-2, GSK-3, Src, ERK-2i or AKT
inhibitor pt formula lie, lie', or 11c", or a
pheunnaceutical composition thereof, in an amount
effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT.

Each of the aforementioned methods directed to
the inhibition of Aurora-2, GSK-3, Src, ERK-2, or AKT, or
the treatment of a disease alleviated thereby, is
preferably carried out with a preferred confound of
formula lie, lie', or lie", as described ^ove.

Another embodiment that is particularly useful
for treating Aurora-2 -mediated diseases relates to
confounds of formula Ild:

lid

or a pharmaceutically acceptable derivative or prodrug

thereof, wherein;
Q' is selected from -C(R®')2-, 1, 2-cyclopropanediyl, 1,2-

cyclobutanediyl, or l, 3-cyclobutanediyl;
R* and are taken together with their intervening atoms
to foarm a fused, unsaturated or partially unsaturated,
5-7 membered ring having 0-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
R* and R^ is independently substituted by oxo, T-r', or
Ii-Z-R^, and each substitutable ring nitrogen of said

• 99-

ring formed by and is independently substituted
by R*;

is T- (Ring D) ;

Ring D is a 5-7 metobered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroarylr
heterocyclyl or carbocyclyl/ said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
s\jbstitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
substituted by -R*;

T is a valence bond or a C1.4 alkylidene chain, wherein
when Q' is -C(R^')2- a methylene group of said C1-4
alkylidene chain is optionally replaced by -0-, -S7,
-N(R*)-, -CO-, -CONH-, -NHCO-, -SO2-. -SO2NH-, -NHSO2-,
-CO2-/ -0C(O)-, -OC(0)NH-, or -NHCO2-;

2 is a Ci-4 alkylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -302N(R^)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C{0)0-,
-N{R^)CON{R^) -, -N(R^) S02N(R^)-, -N (R^) N (R^) - ,
-C(0)N(R^)-, -OC(0)N{R^)-, -C(R^)20-, -C{R^)2S-,
-C(R^)2S0-, -C(R^)2S02-, -C(R^)2S02N{R^)-, -C (R^) 2N(R^) - ,
-C(R^)2N(R^)C(0)-, -C(R^)2N{R^)C{0)0-, -C (R^) =NN (R^) - ,
-C(R^)=N-0-, -CCR^)2N{R^)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C (R^) 2N (R^) CON (R^) - ;

R^ and R^' are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
r2 and R^' is independently substituted by halo, 0x0,

-100-

-CN, -NO2/ -R'» or -V-R^, and each sxabstitutable ring
nitrogen of said ring formed by and R^' is
independently substituted by R*;
r' is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
5 -COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -S(0)2R/ -SR,

-N(R*)2/ -C0N(R'')2, -S02N(r')2/ -0C(=0)R, -N(R'')C0R,
-NCR') C02(Ci.6 aliphatic) , -N(R*)N(R*)2, -C=NN(R*)2,
-C-N-OR, -N(R*')C0N(R')2, -N(R'')S02N(R'')2/ -N{R*)S02R/ ©r

-oc(=o)n{r'')2;

10 each R is independently selected from hydrogen or an
optionally substituted group selected from C1.6
aliphatic, Cs-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

15 each R* is independently selected from -R', -COR',

-CO2 (optionally substituted Ci-s aliphatic) , -C0N(r"')2,
or -SO2R';

each R* is independently selected from -R, halo, -OR,

-C(=0)R, -CO2R, -COCQR, -NO2, -CN, -S(0)R, -SO2R, -SR,

20 -N(R*)2, -C0N(R*)2/ -S02N(R*)2, -0C(=0)R, -N(R*)CX)R,

-N(R*) CO2 (optionally sxibstituted Ci-s aliphatic) ,
-N(R*)N(R*)2, -C=NN(R*)2, -C=N-0R, -N(R*)C0N(R*)2,
-N(R*)S02N(R*)2/ -N(R*)S02R, or -OC (=0)N{R*) 2;
V is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R^)-,

25 -N(R«)-, -CO-, -CO2-, -N(R^)CO-, -N (R«) C (O) O- ,

-N (R«)CON(R^)-, -N(R^)S02N(R«)-, -N (R^)N(R^) - ,
-C(0)N(R*)-, -OC(0)N(R*)-, -C(R^)20-, -C(R^)2S-,
-C(R«)2SO-, -C(R^)2S02-, -C(R«)2S02N(R^)-, -C (R^) 2N (R*) - ,
-C(R«)2N(R*)C(0)-, -C(R^)2N(R^)C(0)0-, -C (R*) =NN(R«) - ,

30 -C(R^)=N-0-, -C(R^)2N(R^)N(R*)-, -C (R*)2N (R^) SOgN (R*) - , or

-C (R^) 2N (R^) CON (R^) - ;
W is -C(R*)20-, -C(R^)2S-, -C(R^)2SO-, -C(R^)2S02-, .
-C (R^) 2S02N(R*) - , -C (R*) 2N(R^) - , -CO- , -CO2- ,

-101-

-C(R^)OC(0)-, -C(.R^)OC(0)N(R^)-, -C (R^) 2N (R^) CO- ,
-C(R^)2N(R^)C{0)0-, -C(R^)=NN(R^)-, -C JR^) =N-0- ,
-C (R«) 2N (R«)N(R^) - , -C (R^) 2N (R^) SO2N (R^) - ,
-C(R^)2N(R^)C0N(R^)-, or -CON(R^)-;

each R^ is independently selected f rom hydrogen or an
optionally substituted C1.4 aliphatic group, or ^wo R^
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;

each R^' is independently selected from hydrogen or a C1-4
aliphatic group, or two R^' on the same carbon atom are
taken together to form a 3-6 membered oarbocyclic ring
and

each r' is independently selected from hydrogen or an
optionally substituted C1.6 aliphatic group, or two R''
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring,

Preferred rings formed by R^ and R^ include a
5-^ e-^ or 7-membered vinsaturated or partially
xinsaturated ring having 0-2 heteroatoms, wherein said
rVR^ ring is optionally substituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula
Ild are shown below.

Ild-A Ild-B Ild-C

-102-

Zld-W

More preferred pyrimidine ring systems of
formula Ild include Ild-A, lld-B, Ud-D, Ild-E, Hd-J,
Ild-P, and Ild-V, most preferably Ild-A, Ild-B, lld-D,
lld-E, and Ild-J.

The ring formed when and of formula lid
are taken together may be sxabstituted or unsubstituted.
Suitable siabstituents include -R, halo, -O (CH2) 2-4-N(R*) 2
-0(CHa)2.4-R, -OR, -N(R*)- (CH2)2.4-N(R*)2/ -N(R*) - (Caiz) 2-4-R

-103-

-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -CON(R*)2, -S02N(R*)2/ -OC<=0)R, -N(R*)COR,
-N(R*)C02(9Ptionally siibstituted Ci-e aliphatic) ,
-N(R*)N(R*)2, -C=NN(R*)2, -C»N-OR, -N(R*)CON(R*) 2,
5 -N{R*)S02N(R*)2, -N(R^)S02R, or -0C(-0)N(R*).2, R and R* are
as defined above. Preferred rVR^ ring sxjbstituents
include -halo, -R, -OR, -COH, -CO2R, -CON(R*)2, -CN,
-0{CHa)2.4-N(R*)2, -0{CH2)2.4-R, , -NO2 -N{R*)2, -NR*COR,
-NR'*S02R, -S02N(R*)2 wherein R is hydrogen or an. cptionally

10 substituted Cx-s aliphatic group.

The R^ and R^' groups of formula lid may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimidb,

15 and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula Ild
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R*/R^' -fused ring
of formula lid include one or more of the following:
-halo, -N(R*)2, -Ci-4 alkyl, -C1.4 haloalkyl, -NO2, -0(Ci-4
25 alkyl) , -CO2 (Ci_4 alkyl) , -CN, ' -SO2 (C1.4 alkyl) , -SO2NH2,
-0C(0)NH2, -NH2S02(Ci-4 alkyl) , -NHC (O) (Cx.4 alkyl) ,
-C(0)NH2, and -CO (C1.4 alkyl) , wherein the (C1-4 alkyl) is a

-104-

Straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl.

When the pyrazole ring system of formula lid is
monocyclic/ preferred groups include hydrogen or a
5 substituted or unsubstituted group selected from aryl,
heteroaryl, or a Ci-€ aliphatic group. Examples of such
preferred groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i -propyl, cyclopentyl, hydroxypropyl ,
methoxypropyl , and benzyloxypropyl. A preferred R^' group

10 is hydrogen.

When Ring D of formula Ild is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula lid is bicyclic,

15 preferred bicyclic Ring D groups include naphthyl,

tetrahydronaphthyl , indanyl , benzimidazolyl , quinolinyl ,
indolyl, isoindolyl, indolinyl, benzo [b] f uryl ,
benzo [b] thiophenyl , indazolyl , benzothiazolyl ,
, cinnolinyl, phthalazinyl, quinazolinyl, quinoacazolinyl ,

20 1, 8-naphthyridinyl and isoquinolinyl .

On Ring D of formula lid, preferred T-R^ or V-2-
r5 substituents include -halo, -CN, -NO2/ -N(R*)2#
optionally sxibstituted Ci-s aliphatic group, -OR, -C(0)R,
-CO2R, -CONH(R*), -N(R*)COR, -N{R*)C02R, -S02N(R*)2r

25 -N(R*)S02R, -N(R^)COCH2N(R^)2, -N(R^)<:OCH2CH2N(R*) 2r and
-N(R^)COCH2CH2CH2N(R*)2/ wherein R is selected from
hydrogen, Ci-s aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred substituents include -Cl, -Br, -F, -CN,

30 -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAC, -NHS02Me,

-NHS02Et, -NHS02(n-propyl) , -NHSO2 (isopropyl) , -NHCOEt, -
-NHCOCH2NHCH3 , -NHCOCH2N (C02t-Bu) CH3 , -NHGOCH2N (CH3) 2 /

-NHCOCH2CH2N (CH3) 2/ -NHCOCH2CH2CH2N (CH3) 2f

-105-

-NHCO (cyclopropyl) , -NHCO (isobutyl) , -NHCOCH2 (inorpholin-4-
yl ) , -NHCOCH2CH2 (morpholin-4 -yl ) , -NHCOCH2CH2CaJ2 (morpholin-
4-yl), -NHC02 (t -butyl ) , -NH(Ci-4 aliphatic) suc!h as -NHMe,
-N(Ci-4 aliphatic) 2 such as -NMe2, OH, -0{Ci-4 aliphatic)
5 such as -OMe^ Cr.-4 aliphatic such as methyl, -ethyl,
cyclopropyl, isopropyl, or t-butyl, and -G02(Ci.4
aliphatic) • .

Preferred Q' groups of formula Ild include
-C(R^')2- or 1,2-cyclopropanediyl, wherein each R^' is
10 independently selected from hydrogen or methyl. A more
preferred Q' group is -CH2-.

Preferred formula lie compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
15 (a) and R^ are taken together with their

intervening atoms to form a fused, xinsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
20 ring carbon of said fused ring formed by R"^ and

R^ is independently substituted by 0x0, T-R^, or
L-Z-R^, and each siibstitutable ring nitrogen of O
said ring formed by R* and R^ is independently
substituted. by R^;
25 (b) R^.is T- (Ring D) , wherein T is a valence bond or

a methylene unit and wherein said methylene unit
is optionally replaced by -0-, -NH-, or -S-;

(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicydic ring selected from an

30 aryl or heteroaryl ring;

(d) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
substituted benzo ring; and

-106-

(e) is selected from -R, -halo, -OR, or -N(R*)2.
More preferred compounds of formula lie have
one or more, and more preferably all, of the featxires
selected from the group consisting of:

(a) R'^ and R^ are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;

(b) R^ is T- (Ring D) , Wherein T is a valence bond or
a methylene unit and wherein said methylene unit
is optionally replaced by -0-, and Ring D is a
5-6 membered monocyclic ring or an 8-10 membered
bicyclic ring selected from an aryl. or
heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci.e aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;

(d) is selected from -R, -halo, -OR, or -N(R*)2#
wheredn R is selected from hydrogen, Cx-s
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R^)-; and

(e) Q' is -C(R^')2- or 1, 2-cyclopropanediyl , wherein
each R^' is independently selected from hydrogen
or methyl .

Even more preferred compoimds of formula lie
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R^ and R^ are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;

(b) R^ is T-Hing D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

-107-

(c) is hydrogen or C1.4 aliphatic and R^' is
hydrogen;

(d) R^ is selected from -R, -OR, or -N(R*)2, wherein
R is selected from hydrogen, Ci-s aliphatic, 5-6
membered het^rocyclyly phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-;

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R*)2/ optionally sijbstituted Ci-6 aliphatic
group, -OR, -C(0)R, -CO2R. -CONH(R^), -N(R*)COR,
-N(R*)C02R, -S02N(R*)2/ -N(R*)S02R,
-N(R^)COCH2N(R^)2, -N{R^)COCH2CH2N(R*)2, or
-N(R^)COCH2CH2CH2N(R*)2, wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(f ) is -CH2-.

Representative compounds of formula Ild are

shown below in Table 4.
Table 4 .

IId-1 IId-2 IId-3

IId-13 IId-14 IId-15

-109-

IId-19

In another embodiment, this invention provides
a composition comprising a compoiind of formula Ild and. a
pharmaceutically acceptable carrier.

j?toother aspect of this invention relates to a
method of treating or preventing an Aurora -2 -mediated
disease with an Aurora-2 inhibitor, which method
con5>rises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula lid or a pharmaceutical composition
thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora- 2 activity in a patient,
which method comprises administering to the patient a
compound of formula Ild or a con5>osition comprising said
compound.

Another aspect of this invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

-110-

therapeutically effective amount of a compound of formula
Ild or a pharmaceutical composition thereof.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering.
5 blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amoimt of a con5)Ound of formula
lid or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another

10 method relates to inhibiting the production of

hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for

15 treating schizophrenia.

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, whi<:h
method comprises administering to the patient a con5)o\md
of formula lid or a composition comprising said compound.

20 Another method relates to inhibiting Aurora- 2

or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula lid, or a
pharmaceutical composition thereof, in an amount

25 effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula lid, as described

30 above.

Another embodiment of this invention relates to
compoxinds of formula Ilia:

-111-

r2

Ilia

or a pharmaceutically acceptable derivative or prodrug
5 thereof, wherein:

and are independently selected from T-R^ or L-Z-R^;
R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
10 heterocyclyl or carbocyclyl, said heteroaryl or

heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen / oxygen or sulfur, wherein each
subs ti tut able ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R®, and each
15 substitutable ring nitrogen of Ring D is independently

substituted by -R^;
T is a valence bond or a C1-4 alkylidene chain;
Z is a Ci-4 alkylidene chain;

L is -0-, -SO-, -N(R^)S02-, -SOzNCR^)-,

20 -N{R^)-, -CO-, -CO2-/ -N(R^)CO-, -N (R^)C (O) O- ,

-N(R^)CON(R^)-, -N(R^)S02N(R^)-, -N (R^}N (R^) - ,
-C(0)N(R^)-, -OC (O)N(R^)-, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R^)2S02-/ -C(R^)2^02N(R^) -C (R^) 2N (R^) - ,
-C(R^)2N{R^)C(0)-, -C(R^)2N(R^)C(0)0-, -C (R^) =NN (R^) - ,
25 -C(R^)=N-0-, -C(R^>2N(R^) N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or

-C (R^) 2N (R^) CON (R^) - ;
R^ and R^' are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, imsaturat-ed or

-112-

partially unsaturated, ring having 0-3 ring hetaroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
aoid R^' is independently substituted by halo, oxo,
5 -CN, — NO2/ or -V-R^, and each substitutable ring

nitrogen of said ring formed by R^ and R^' is
independently substituted by R*; ■
R^ is selected from -R, -halo, -OR, -C(»0)R, -CO2R/
-cocoR, -COCH2COR, -NO2, -casi, -S(0)R, -S(0)2R, -SR,

10 -N{R*)2/ -CON(R*')2, -S02N(R')2/ -0C(=0)R, -N(r')COR,

-NCR'') CO2 (C1.6 aliphatic) , -N(R*)N(R*)2, -C=NN(R*)2,
-C=N-OR, -N(R')C0N(R')2/ -N(R'')S02N(R*')2> -N(R*)S02R, or

-oc{=o)n(r')2;

each R is independently selected from hydroge^n or an
15 optionally sxabstituted group selected f arom Ci-s

aliphatic, Cc-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R* is independently selected from -r', -GOR',
20 -CO2 (optionally siabstituted Ci-6 aliphatic) , -C0N(R"')2#

or -SO2R';

each R* is independently selected from -R, halo, -OR,
-C{=0)R, -CX52R/ -COCOR, -NO2/ -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -C0N(R*)2, -S02N(R*)2/ -OC(-0)R> -N(R*)COR,

25 -N(R'*)C02 (optionally siabstituted Ci_6 aliphatic) ,

-N(R*)N(R*)2, -C=:NN(R*)2, -C=N-OR, -N(R*) CON(R*)2,
-N(R*)S02N(R*)2, -N(R*)S02R, or -6C(=0)N(R*)2;
V is -0-, -S-, -SO-, -SO2-, -N(R^)SOa-, -S02N(R^)-,
-N(R^)-, -CO-, -CO2-/ -N(R^)C0-, -N(R^)C(0)0-,

30 -N(R^)CON{R^)-, -N(R*)S02N(R«)-, -N (R^)N (R^) - ,

-C(0)N{R^)-, -OC(0)N(R^) -, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R^)2S02-, -C{R^)2S02N(R«)-, -C (R«)2N(R®)
-C(R^)2N(R^)C(0)-, -C(R^)2N(R^)C(0)0-, -C (R*) =NN(R*) - ,

-113-

-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C (R^) 2N (R^) CON (R^) ;

W is -C(R^)20-, -C(R^)2S-, -C(R^)2SO-, -C(R^)2S02-,
-C(R^)2S02N(R^) -C(R^)2N(R^)-, -CO-, -CO2-,
-C(R^)OC(0)-, -C(R^)OC(0) N (R^)-, -C (R^) 2N (R^) CO- ,
-C(R^)2N(R^)C(0)0-, -C{R^)=NN(R^)-, -C<R^)=N-0-,
-C (R^) 2N.(R^) N (R^) - , -C (R^) 2N (R^) SO2N (R^) - ,
-C(R^)2N(R^)CON(R^)-, or -CON(R^)-;

each R^ is independently selected from hydrogen or an
optionally siibstituted C1-4 aliphatic group, or two R^
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and

each r"' is independently selected from hydrogen or an
optionally substituted Ci-e aliphatic group, or two R''
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.

Preferred R* groups of foznaula Zlla include

hydrogen, alkyl- or dialkyl amino, acetamido, or a C1-4

aliphatic group such as methyl, ethyl, cyclopropyl# or

isopropyl.

Preferred R^ groups of formula Ilia include T-R^
or L-Z-R^ wherein T is a valence bond or a methylene, L is
-0-, -S-, or -N(R^)-, -C(R^)20-, -GO- and R^ is -R,
-N(R^)2/ or -OR* Examples of preferred R^ groups include
2 -pyridyl , 4 -pyridyl , pyrrolidinyl , piperidinyl ,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl- or dialkylamino such as ethylamino
or dimethylamino, alkyl- or dialkylaminoalkoxy such as

•114-

dimethyl aminopropyloxy, acetamido, optionally sxibstituted
phenyl such as phenyl or halo-substituted phenyl.

The and R^' groups of formula Ilia may be
taken together to form a fused ring, thus providing a
5 bi cyclic ring system containing a pyrazole ring.

Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula Ilia
compounds having a pyrazole -containing bicyclic ring
10 system:

Preferred substituents on the R^/R^' fused ring
15 of formula Ilia include one or more of the following :
-halo, -N(R^)2/ -Ci.4 alkyl, -CI-* haloallcyl, -0«:i-4
alkyl) , -CO2 (Ci,4 alkyl) , -CN, -SO2 (C1-4 alJcyl) , -S02lHl2#
-0C(0)NH2, -NH2S02(Ci.4 alkyl) , -NHC<0) (C1-4 alkyl) ,
-C(0)NH2/ and -CO (C1.4 alkyl) , wherein the (C1.4 alkyl) is a
20 straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl.

When the pyrazole ring system of formula Ilia
is monocyclic, preferred groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
25 heteroaryl, or a Ci-g aliphatic' group. .Examples of such
preferred R^ groups include H, methyl, ethyl, propyl, ,
cyclopropyl , i -propyl , cyclopentyl , hydroxypropyl ,

-115-

methoxypropyl , and benzyloxypropyl • A preferred R^' group
is hydrogen.

When Ring D of formula Ilia is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
5 pyridazinyl, pyrimidinyl, cuid pyrazinyl.

When Ring D of formula IXIa is bicyclic,
preferred bi cyclic Ring D groups include naphthyl/
tetrahydronaphthyi , indanyl, benzimidazolyl , quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b] f uryl ,

10 benzo [b] thiophenyl , indazolyl, benzothiazolyl , ^
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl.

On Ring D of formula ZXIa, preferred T-R^ or V-
Z-R^ substituents include -halo, -CN, -NO2/ -N(R*)2/

15 optionally substituted Ci-e aliphatic group, -OR, -C(0)R,
-CO2R, -GONH(R*), -N(R*)COR, -N(R*)C02R. -S02N(R*)2,
-N{R^)S02R, -N(R^)COCH2N{R*)2, -N (R®) GOCH2CH2N (R*) 2, and
-N(R^)COCH2CH2CH2N(R^)2, wherein R is selected from
hydrogen, Ci.e aliphatic, phenyl, a 5-6 membered

20 heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred sxabstituents include -Cl, -Br, -F, -CN,
-CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, 1.,?
-NHS02Et, -NHSO2 (n-propyl) , -NHSO2 (isopropyl) , -NHCOEt,-
-NHCOCH2NHCH3 , -NHCOCH2N (COst-Bu) CH3 , -NHGOCH2N (CH3) 2i

25 -NHCOCH2CH2N (CH3) 2 / -NHCOCH2CH2CH2N (CH3) 2 ,

-NHCO ( cyclopropyl ) , -NHCO ( isobutyl ) , -NHCOCH2 (morpholin-4 -
yl) , -NHCOCH2CH2 (morpholin-4 -yl) , -NHCOCH2CH2CH2 (morpholin-
4-yl) ^ -NHCO2 (t -butyl ) , -NH(Ci-4 aliphatic) such as -NHMe,
-N(Ci^4 aliphatic) 2 such as -NMe2/ OH, -0(Ci.4 aliphatic)

30 such as -OMe, Cx-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and -C02(Ci-4
aliphatic) .

-116-

Preferred formula Xlla compoiinds have one or
more, and more preferably all, of the features selected
from the group corisi siting of:

(a) is hydrogen, alkyl- or dialkyl amino,
5 acetamido, or a C1-4 aliphatic group; •

(b) is T-R^ or L-Z-R^, wherein T is a valence bond
or a methylene and R^ is -R, -N{R*)2*/ or -OR;

(c) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene tinit;

10 (d) Ring D is a 5-7 membered monocyclic or an 8-10

membered bicyclic aryl or heteroaryl ring; and
(e) R^ is -R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are taken together to form an optionally
substituted benzo ring.
15 More preferred compounds of formula IlZa have •

one or more, and more preferably all, of the features
selected from the group consisting of :

(a) R^ is T-R^ or I*-Z-R^ wherein T is a valence bond
or a methylene euid R^ is selected from -R, -OR,

20 or -N(R*)2/ wherein R is selected from hydrog«i,

Ci-6 aliphatic, or 5-6 membered heterocyclyl ,
phenyl, or 5-6 membered heteroaryl;

(b) R^ is T- (Ring D) , wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10
25 membered bicyclic aryl or heteroaryl ring;.

(d) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci^e aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

30 (e) L is -0-, -S-, or '-N(R*)-.

Even more preferred compounds of f oannula Ilia
have one or more, and more preferably all, of the
features selected from the group consisting of:

-uv-
ea) is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido;

(b) is selected from 2-pyridyl, 4-pyridyl,
pyrrol idinyl , piper idinyl , morpholinyl ,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl , t-butyl , alkoxyalkylamimo , .
alkoxyalkyl, alkyl- or dialkylamino; alkyl- or
dialkylaminoalkoxy, acetamido, optionally
sxibstituted phenyl, or methoxymethyl ;

(c) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from -halo, -CN,
-NO2, -N{R*)2, optionally stabstituted C1.6
aliphatic group, -OR, -CO2R, -CONH(R*) ,
-N(R*)COR, -N{R*)S02R, -N(R^) COCH2CH2N<R*)2r or
-N(R^)COCH2CH2CH2N(R*)2; and

(d) R^ is hydrogen or a substituted or unsxjbstituted
Ci-s aliphatic, and L is -0-, -S-, or -NH-.

Representative compounds of formula IlZa are
shown below in Table 5.

Table 5.

IIIa-1

IIIa-2

IIIa-3

IIIa-13

Ilia- 14

IIIa-15

IIIa-28

IIIa-29

.IIIa-30

-120-

IIIa-40

IIIa-41

IIIa-42

-121-

IIla-55 IIIa-56 IIIa-S7

-122-

IIIa-61 IIIa-62 IIIa-63

In another embodiment^ this invention provides
a composition comprising a compound of formula Ilia and a
pharmaceutically acceptable carrier.

Another aspect of this invention relates to a
method of treating or preventing an Aurora -2 -mediated
disease with an Aurora-2 inhibitor, which, method
comprises administering to a patient in need of -such a
treatment a therapeutically effective amount of a
compound of formula Ilia or a pharmaceutical con5>osition
thereof .

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a pati^ent,
which method comprises administering to the patient a
con^oxand of formula Ilia or a composition comprising said
compound.

-123-

Another aspect of this invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
5 therapeutically effective araoxmt of a compound of formula
Xlla or a pharmaceutical composition thereof.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,

10 which method comprises a.dministering to the patient a

therapeutically effective amount of a coiiqpound of formula
Zlla or a pharmaceutical composition thereof- This
method is especially useful for diabetic patients.
Another method relates to inhibiting the production of

15 hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for
treating schizophrenia. ^ -

20 Another aspect of this invention relates to a

method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula Ilia or a composition comprising said
compound.

25 Another aspect of this invention relates to a

method of treating or preventing a Sro-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula

30 IZIa or a pharmaceutical composition thereof.

Another aspect of the invention relates to
inhibiting Src activity in a patient, which method

-124-

comprises administering to the patient a compound of
formula Xlla or a composition comprising said compound.

Another method relates to inhibiting Aurora-2,
GSK-3, or Src activity in a biological sample, which
5 method comprises- contacting the biological sample with

the Aurora-2, GSK-3, or Src inhibitor of formula Ilia, .or
a pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2, GSK-3, or Src.

Each of the aforementioned methods directed to
10 the inhibition of Aurora- 2, GSK-3, or Src, or the

treatment of a disease alleviated thereby, is preferably
carried out with a preferred compound of formula Ilia, as
described above.

Another embodiment of this invention relates to
15 compounds of formula I lib:

R

NH

lllb

20 or a pharmaceutic ally acceptable derivative or prodrug
thereof, wherein:

and are independently selected from T-R^ or L-Z-R^;
R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or B-10 membered
25 bicyclic ring selected from aryl, heteroaryl,

heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently

-125-

substitut.ed by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
siibstituted by -R*;

T is a valence bond or a C1-4 alkylidene chain;

Z is a C1.4 allcylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R*)S02-, -SOaN(R*)-,
-N{R*)-, -CO-, -CO2-, -N(R*)CO-, -N(R*)C(0)0-,
-N(R^)CON (R*)-, -N{R*)SOaN(R*)-, -N(R*)N(R*)
-C(0)N(R'')-, -0C(0)N(R*)-, -C{R*)20-, -C(R*)2S-,
-C(R*)2SO-, -C(R«)2S02-, -C(R*)2Sp2N(R«)-, -C (R«) 2N (R*) - ,
-C(R^)2N(R*)C(0)-; -C(R*)2N{R*)C(0)0-, -C (R*) =NN(R*) - ,
-C(R*)=N-0-, -C(R^) 2N(R«)N(R«)-, -C (R*) 2N (R*) S02N (R*) - , or
-C (R* ) 2N (R*) CON (R«) - ;

R^ and R*' arie independently selected from -R, -T-W-R*, or
R* and R^' are taken together with ^Jaeir intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially xmsatxirated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ri.ag formed by
r2 and R^' is independently substituted by halo, 0x0,
-CN, -NO2, -R'/ or -V-R®, and each substitutable ring
nitrogen of said ring formed by R^ auid R^' is
independently stabs ti tut ed by R"*;

R^ is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -S(0)2R, "SR,
-N{R*)2, -C0N{R')2, -S02N{R'')2, -0C(=0)R, -N(R'')C0R,
-N(r'')C02{Ci.6 aliphatic) , -N(R*).N(R*)2, -C=NN(R*).2,
-C=N-0R, -N(R')C0N(R'')2, -N(R')S02N(R'')2, -N(R*)«02R, or

-oc(=o)n(r')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Cx-e
aliphatic, Cg-io aryl, a heteroaryl ring having 5-10

-126-

ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ;

each R* is independently selected from -r', -COR',

-CO2 (optionally substituted Ci.6 aliphatic) , -<X)N(R')2#

5 or -SO2R'';

each R* is independently selected from -R, halo, -OR,
-c{=o)R, -CO2R, -cocoR, -NO2, -car, -s(o)R, -SO2R, -sr,

-N{R*)2, -CON(R*)2/ -S02N(R*)2, -OC(=0)R, -N(R*)C<»,
-N(R*)C02 (optionally substituted Ci-6 aliphatic) ,

10 -N(R*)N(R*)2, -C=NN(R*)2, -C=N-OR, -N (R*) CON (R*) 2/

-N(R*)S02N(R*)2/ -N(R*)Sp2R, or -OC (-O)N(R*) 2;
V is -0-, -S-, -SO-, -SO2-, -N(R*)S02-# -S02N(R*)-,
-N(R*)-, -CO-, -CO2-, -N(R*)CO-, -N(R*)C<0)0-,
-N(R*)CON(R*)-, -N(R*)S02N(R«) -, -N (R*) N(R'') - ,

15 -C(0)N(R*)-, -OC(0)N(R«)-, -C(R*)20-, -C(R*).2S-,

-C(R*)2S0-, -C(R«)2S02-, -C(R^) 2SOiN(R'')-, -C (R*) 2N (R^) - ,
-C(R*)2N(R*')C(0)-, -C(R«)2N(R*)C (0)0-, -C (R«) =NN (R") ,
-C(R^)-N-0-, -C(R*)2N(R*)N(R*)-, -C(R«)2N(R*)S02N(R*)-, or
-C (R* ) 2N (R* ) CON (R* ) - ; "

20 W is -C(R*)20-, -C(R*)2S-, -C(R*)2SO-, (R*) 2SO2- ,
-C(R*)2S02N(R*) -, -C(R*)2N(R*)-, -CO-, -CO2-,
-C(R^)OC(0)-., -C(R*)OC{0)N(R*) -, -C (R*) 2N(R*) CO- ,
-C(R^)2N(R^)C(0)0-, -C(R*)=NN(R«) -, -C(R*)«N-0-,
-C(R^)2N(R^)N(R*)-, -C(R*)2N(R^)S02N(R*)-,

25 -C(R^)2N(R*)C0N(R^)-, or -CON(R^)-;

each R^ is independently selected froni hydrogen or an
optionally substituted Ci:4 aliphatic group, or two R*
groups on the same nitrogen atom are taken together
with the nitrogen atom. to form a 5-6 membered

30 heterocyclyl or heteroaryl ring; and

each r"' is independently selected from hydrogen or an
optionally substituted Ci-g aliphatic group, or two r'^
on the same nitrogen are tedcen together with the '. .

-127-

nitrogen to form a 5-8 metnbered heterocyclyl or
heteroaryl ring.

Preferred groups of formula XlXb include -
hydrogen, alkyl- or diallcylamino, acetamido, or a Ci.4
5 aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.

Preferred R?" groups of formula Illb include T-R^
or L-Z-R^ wherein T is a valence bond or a methylene, L is
-S-, or -N(R*)-, -C(R^)20-, -CO- and R^ is -R,

10 -N(R*)2r or -OR* Examples of preferred R^ groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl , piperidi^yl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl ot

15 methoxyethyl , alkyl- or dialkylaminb «uch as ethylamino
or dimethylamino, aikyl- or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo- substituted phenyl.

The R^ and R^' groups of formula IlZb may be

20 taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered <:arbocyclo ring.
These are exemplified in the following foarmula Illb

25 compounds having a pyrazole -containing bicyclic ring
system:

-128-

Preferred substituents on the R^/R^' fused ring
of formula 1 1 lb include one or more of the following:
-halo, -N(R*)2, -Ci-4 alkyl, -C1.4 haloalkyl, -NO2, -0(Ci.4
5 alkyl), -CO2 (C1.4 alkyl) , -CN, -SO2 (C1-4 alkyl) , ■ -SO2NH2,
-0C(6)NH2, -NH2S02(Ci-4 alkyl) , -NHC (O) (C1.4 alkyl) ,
-C(0)NH2/ and -CO (Ci-4 alkyl) , wherein the (C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl.

10 When the pyrazole ring system of formula IXXb

■3 is monocyclic, preferred R^ groups include hydrogen or a

substituted or unsubstituted group selected from aryl,
heteroaryl, or a Ci-s aliphatic group. Examples of such
preferred R^ groups include H, methyl, ethyl, propyl, ,

15 cyclopropyl, i -propyl, cyclopentyl, hydroxj^ropyl ,

methoxypropyl , and benzyloxyprc^yl . A preferred R^' group

is hydrogen.

When Ring D of formula IZIb is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
20 pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula Illb is bicyclic,
J preferred bicyclic Ring D groups include naphthyl,

tetrahydronaphthyl, indanyl, benzimidazolyl , quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b] furyl,
25 benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

cinnolinyl, phthalazinyl , quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl.

On Ring D of formula Illb, preferred T-R^ or
V-Z-R^ substituents include -halo, -CN, -NO2/ -N(R*)2>
30 optionally substituted C1.6 aliphatic group, -OR, -C{0)R,
-CO2R/ -CONH(R^), -N(R^)COR, -N(R^)C02R, -S02N(R*)2,
-N(R*)S02R, -N(R^)COCH2N{R^)2, -N (R^) COCH2CH2N (R^) 2, and
-N(R^)COCH2CH2CH2N(R*)2y wherein R is selected from

-129-

hydrogen, Ci-e aliphatic, phenyl, a 5-^ membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred sxibstituents include -Cl, -Br, -F, -CN,
-CF3, -COOH, -CONHMe, -CONHEt, -NHar -NHAc, -NHS02Me,
-NHS02Et, -NHS02(n-propyl) , -NHSO2 (isoprppyl) , • -NHCOEt,
-NHCOCH2NHCH3, -NHCOC3a2N(C02t-Bu) CH3, -NHCOGH2N (CH3) 2/
-NHCOCai2CH2N ( CH3 ) 2 / -NHCOCH2CH2CH2N ( CH3 ) 2 r

-NHCO ( cyclopropyl ) , -NHCO ( isobutyl ) , -NHCOCH2 {morpholin-4 -
yl ) , -NHCOCH2CH2 (morpholin-4 -yl ) , -NHCOCH2CH2CH2 (morpholin-
4-yl), -NHCO2 (t -butyl ) , -NH(Ci:.4 aliphatic) such as -NHMe,
-N(Ci-4 aliphatic) 2 such as -NMe2/ OH, -0(Ci.4 aliphatic)
such as. -OMe, Cx-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t- butyl, and -G02(Cx-4
aliphatic) .

Preferred formula XXIb compoxjnds have one or
more, and more preferably all, of the features selected
from the group consisting of:

(a) R* is hydrogen, alkyl- or dialkylamino,
acetamido, or a C1-4 aliphatic group;

(b) R^ is T-R^ or L-Z-R^, wherein T is a valence bond
or a methylene and R^ is -R, -N(R*)2/ or -OR;

(c) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10
.membered bicyclic aryl or heteroaryl ring; and

(e) R^ is -R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are taken together to foim an optionally
substituted benzo ring.

More preferred compounds of formula IXIb have
one or more, euad more preferably all, of the features
selected from the group consisting of:

(a) R^ is T-R^ or L-Z-R^ wherein T is a valence bond
or a methylene and R^ is selected from -R, -OR,

-130-

or -N(R^)2/ wherein R is selected from hydrogen,
Ci-c aliphatic, or 5-6 metnbered heterocyclyl #
phenyl, or 5-6 membered heteroaryl;

(b) is T- (Ring D) , wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;

(d) R^ is.-R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-6. aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a S-6 membered
heterocyclic ring; sund

(e) L is -0-, -S-, or -N{R*)-.

Even more preferred compoxinds of formula Illb
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R^ is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido;

(b) R^ is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl/ methyl, ethyl, cyclopropyl,
i sopropyl , t -butyl , alkoxyalkyl amino ,
alkoxyalkyl, alkyl- or dialkylamino, alkyl- or.
dialkylaminoalkoxy, aoetamido, optionally
substituted phenyl, or methoxymethyl ;

(c) R^ is T- (Ring D) , wherein T is a valence bond ^d
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally stibstituted
with one to two groups selected from -halo, -CN,
-NO2, -N(R^)2# optionally substituted Ci^s
aliphatic group, -OR, -CO2R, -CONH(R^) ,
-N(R^)COR, -N(R^)S02R, -N (R^) COCH2CH2N (R*) 2. or
-N(R^)COCH2CH2CH2N(R*)2; and

-131-

(d) is hydrogen or a substituted or unsubstituted
Ci-e aliphatic, and L is or -NH- .

Representative compounds of formula Illb are
shown below in Table ۥ

(

Table 6.

N

IIIb-1 IIIb-2 IIIb-3

IIIb-4 IlIb-5 IIIb-6

IIIb-7 IlIb-8

«

-132-

Me Me Me

IIIb-10 IIIb-11. IIIb-12

IIIb-13 IIIb-14 IIIb-15

lIIb-19 IIIb-20 IIIb-21

IIIb-22 IIIb-23 IIXb-24

-133-

Me ivie Me

JSV" J^"

l-**!^ H NMe2 HN'^N HN'^N

a CI

IIIb-25 IIIb-2^ IIIb-27

Me

Me Me we

^l*^

HN'^N HW^N HN'^N

U^N ff^N rt^N

£5.V-^o-TQ ^r^-^N^o^ ^.0''"^"9

CI

IIIb-28 HIb-29 III±)-30

In another embodiment, this invention provides
a composition comprising a compound of formula Illb and a
pharmaceutically acceptable carrier.

JAnother aspect of this invention relates to a
5 method of treating or preventing an Aurora- 2 -mediated
disease with an Aurora- 2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amotint of a
compound of formula XXIb or a pharmaceutical -composition
10 thereof .

Another aspect of this invention relates to a
method of inhibiting Aurora- 2 activity in a patient,
which method comprises administering to the patient a
compound of formula Illb or a composition comprising said
15 compound.

Another aspect of this invention relates to a
method of treating or preventing a <3SK- 3 -mediated disease
with a GSK- 3 inhibitor, which method comprises

-134-

administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of fomiula
XXib or a pharmaceutical composition ther-eof .

One aspect of this invention relates to a
5 method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of f oirmula
Illb or a pharmaceutical composition thereof. This

10 method is especially useful for diabetic patients.
L3 Another method relates to inhibiting the production of

hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's,
disease. Another method relates to inhibiting the

15 phospho3rylation of p-catenin, which is useful for
treating schizophrenia .

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a -compound

20 of formula IlXb or a composition comprising said
compound.

Another method relates to inhibiting Aurora-2

or GSK-3 activity in a biological sample, which method

comprises contacting the biological sample with the
25 Aurora- 2 or GSK-3 inhibitor of formula Illb, or a

pharmaceutical composition thereof, in an amoxmt

effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to

the inhibition of Aurora-2 or GSK-3, or the treatment of
30 a disease alleviated thereby, is preferably carried out

with a preferred compound of formula Illb, as described

above.

-135-

Another embodiment of this invention relates to
conipoimds of foinaula ZZIc:

HN

H

IIIc

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:

R* and are independently selected from T-r' or L-Z-R^;
10 R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
15 from nitrogen,, oxygen or sulfur, wherein each

substitutable ring carbon of Ring D is independently
stabstituted by oxo, T-R^, or V-Z-R^, and each Q)
substitutable ring nitrogen of Ring D is ind^endently
substituted by -R*;
20 T is a valence bond or a C1-4 alkylidene chain;
Z is a C1.4 allcylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R*)S02-, -S02N{R*)-,
-N{R^)-, -CO-, -CO2-, -N(R*)CO-, -N(R*)C(0).O-,
-N(R^)CON(R^)-, -N(R*)S02N<R*)-, -N (R*)N(R*) - ,
25 -C{0)N(R^)-, -OC(0)N(R^)-, -C(R^)20-, -C(R*)2S-,

-C(R^)2SO-, -C(R^)2S02-, -C(R«)2S02N(R^)-, -C (R^) 2N (R*) - ,
-C(R^)2N{R*)C(0)-, -C(R^)2N(R^)C(0)0-, .-C(R^)=NN(R*)-,

-136-

-C{R^)«N-0-, -C(R^)2N{R^)N.(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C(R^)2N{R^)CON(R^)

R^ and R^' are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
sxibstitutable ring carbon of said fused ring formed by
R^ and R^' is independently substituted by halo, 0x0,
-CN, -N02r -R^# or -V-R®, and each substitutable ring
nitrogen of said ring formed by R^ and R^' is
independently substituted by R*;

R^ is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -SCOaR, -SR,
-N(R*)2, -C0N(R'')2, -S02N(R'')2/ -0C{=:0)R, -N{R'')C0R,
-N{R'')G02(Ci.6 aliphatic) , -N(R*)N(R*) 2. . -C=NN(R*)2/
-C=N-OR, -N(R'')C0N(R^)2, -N{R'')S02N(R'')2, -N(R*)S02R, or
-0C(=0)N(R'')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-e
aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R* is independently selected from -r'', -COR'',

-CO2 (optionally substituted Ci-6 aliphatic) , -C0N(R^)2'/
or -S02R^;

each R^ is independently selected from -R, halo, -OR,

-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R^)2, -CON(R^)2, -S02N(R^)2, -OC{=0)R, -N(R^)COR,
-N(R^)C02 (optionally substituted Ci-e aliphatic) ,
-N{R^)N(R^)2/ -C=NN(R*)2, -C=N-OR, -N (R^) CON (R^) 2 ,
-N(R^)S02N(R*)2, -N(R^)S02R, or -OC (=0)N (R*) 2;

-137-

V is -0-, -S-, -SO-, -SO2-, -N(R*)S02-, -SdaNCR^)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C(0)0-,
-N(R^)CON(R*) -, -N(R«)S02N(R*)-, -N (R*) N (R^) - ,
-C(0)N{R*)-, -0C{0)N(R*)-, -C{R*)20-, -C(R*)2S-,
5 -C(R*)2SO-> -C(R*)2S02-, -C(R^)2S02N(R^)-/ -C (R*)2N(R^) -/

-C(R*)2N(R*)C(0)-, -C(R«)2N(R^)C (0)0-, -C (R«) =NN{R^) - ,
-C(R*)=N-0-, -C {R^) 2N{R*)N(R*)-, -C(R^) (R*) SOzNCR*) - , or
-C (R*) 2N (R*) CON (R*) - ;
W is -C(R*)20-, -C(R*)2S-, -C(R*)2SO-, -C(R«)2S02-,
10 -C(R*)2S02N(R^) -/ -C(R*)aN(R*)-, -CO-, -CO2-,

-C(R^)OC(0) -C(R*)OC(0)N(R*)-, -C (R*) 2N (R*) CO- , @
-C(R*)2N(R*)C<0)0-, -C(R*)=NN(R*) -C (R^) -N-O- , -
-C(R*)2N(R^)N(R*)-, -C(R*)2N(R*)S02N(R*)-,
-C{R*)2N(R*)CON(R*)-, or -CON(R*)-;
15 each R* is independently selected from hydrogen or an

optionally substituted C1.4 aliphatic group, or two R^
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
20 each r'' is independently selected from hydrogen or an

optionally substituted Ci-6 aliphatic group, or two. R'
on the same nitrogen are taken together with the Cj
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
25 Preferred R* groups of formula IXZc include

hydrogen, alkyl- or dialkylamino, acetamido, or a C1.4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl .

Preferred R^ groups of formula IIIc include T-R^
30 or L-Z-R^ wherein T is a valence bond or a methylene, L is
-0-, -S-, or -N(R*)-, -C(R*)20-, -CO- and R? is -R,
-N{R*)2/ or -OR. Examples of preferred R^ groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl , piperidinyl.

-138-

morphol inyl , piperazinyl , methyl , ethyl , cyclopropyl ,
isopropyl, t -butyl, alkoxyalkylamino such as
methoxyethylatitino, alkoxyalkyl such as methoxymethyl or
methoxyethyl , alkyl- or dialkylamino such as ethylamino
5 or dimethylamino, alkyl- or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally siabstituted
phenyl such as phenyl or halo-substituted phenyl.

The euid R*' groups of formula Illc may be
taken together to form a fused ring, thus providing a

10 bicydic ring system containing a pyrazole ring.
(.3 Preferred fused rings include benzo, pyrido, pyrimido,

and a partially tmsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula Illc
con5)o\inds having a pyrazole-containing bicyclic ring

15 system:

Preferred substituents on the R^/R^' fused ring
20 of foimula. Illc include one or more of the following:
-halo, -N(R*)2, -Ci.4 alkyl, -C1-4 haloalkyl, -NO2, -0(Ci-4
alkyl), -C02(Ci-4 alkyl) , -CN, -SO2 (C1-4 alkyl) , -SOiNHz, •
-OC(0)NH2, -NH2S02(Ci.4 alkyl) , -NHC (O) (C1.4 alkyl) ,
-C(0)NH2, and -Cd(Ca.4 alkyl), wherein the tCi-4 alkyl) is a
25 straight, branched, or cyclic alkyl group. Preferably,
the (C1.4 alkyl) group is methyl.

When the pyrazole ring system of formula lllc
is monocyclic, preferred R* groups include hydrogen or a

-139-

sxabstituted or iinsiibstituted group selected from aryl,
heteroaryl , or a Ci-e aliphatic group. Exan5>les of such
preferred groups include H, methyl, jethyl, propyl, ,
cyclopropyl, i -propyl, cyclopentyl, hydroxypropyl ,
5 methoxypropyi, and benzyloxypropyl • A preferred R^' group
is hydrogen.

When Ring D of formula Illc is monocyclic,
preferred Ring D groups, include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

10 When Ring D of formula IXZc is bicyclic,

- • £^

preferred bicyclic Ring D groups include naphthyl, .

tetrahydronaphthyl , indanyl, benzimida^olyl , quinolinyl,

indolyl, isoindolyl, indolinyl, berizo [b] f uryl ,

benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

15 cinnolinyl, phthalazinyl , quinazolinyl , quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl .

On Ring D of formula lllc, preferred T-R^ or
V-Z-R^ substituents include -halo, -CN, -NO2, -N(R*)2#
op::ionally substituted Ci-e aliphatic group, -OR, -C(0)R,

20 -CO2R, -CONH(R*), -N(R*)COR, -N(R^)C02R, -S02N(R^)2/

-N(R^)S02R, -N(R^)C0CH2N(R*)2, -N (R^) COCH2CH2N (R^) 2. and
-N(R^)COCH2CH2CH2N(R*)2, wherein R is selected from O
hydrogen, Ci-e aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.

25 More preferred R^ substituents include -CI, -Br, -F, -CN,
-CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSOzKe,
-NHSO2E t , -NHSO2 ( n-propyl ) , -NHSO2 ( i sopropyl ) , -NHCOEt ,
-NHCOCH2NHCH3, -NHCOeH2N(C02t-Bu)CH3, -NHCOCHaN (CH3) 2,
-NHCOCH2CH2N (CH3)2/ -NHCOCH2CH2CH2N (CH3) a,

30 -NHCO(cyclopropyl) , -NHCO (i^crfautyl) , -NHCOCH2 (morpholin-4-
yl) , -NHCOCH2CH2(moxpholin-4-yl) , -NHCOCH2CH2CH2<morpholin-
4-yl) , -NHCO2 (t -butyl ) , -NH(Ci_4 aliphatic) such as -NHMe,
-N(Ci.4 aliphatic) 2 such as -NMea, OH, -0(Ci.4 aliphatic)

-140-

such as -OMe, C1.4 aliphatic such as methyl, ethyl,
cyclopropyl; isopropyl, or t-butyl, and -C02(Cx-4
aliphatic) .

Preferred formula ZJIc compounds have one or
5 more, and more preferably all, of the features selected
from the group consisting of:

(a) R*" is hydrogen, alkyl- or dialkylamino,
acetamido, or a C1.4 aliphatic group;

(b) is T-R^ or L-Z-R^ wherein T is a valence bond
10 or a methylene and R^ is -R, -N(R*)2# or -OR;

(c) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aaryl or heteroaryl ring; and

15 (e) r2 is -R or -T-W-R^ and R^' is hydrogen, or R^ and

R^' are taken together to form an optionally
substituted benzo ring.
More . preferred compounds of foarmula IXIc have
one or more, and more preferably all, of the features
20 selected from the group consisting of:

(a) R^ is T-R^ or L-Z-R^ wherein T is a valence bond
or a methylene and R^ is selected from -R^ -OR,
or -N(R^)2/ wherein R is selected from Ci-€
aliphatic, or 5-6 membered heterocyclyl , phenyl,

25 or 5-6 membered heteroaryl;

(b) R^ is T- {Ring D) , wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;

(d) R^ is -R and R^' is hydrogen, wherein R. is

30 selected from hydrogen, Ci-g aliphatic, phenyl, a

5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(e) L is -0-, -S-, or -N(R^)-.

-141-

Eyen more preferred compoiands of formula IIZc
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R"* is hydrogen methyl, ethyl, propyl,
cyclbpropyl, isopropyl, methylamino or
acetimido;

(b) is selected from 2-pyri<ayl, 4-pyridyl,
pyrrol idinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkyl amino,
alko3<yalkyl, alkyl- or dialkylamino, alkyl- or
diallcylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl ;

(c) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from -halo, -CN,
-NO2, -N(R*)2/ optionally substituted Ci-e
aliphatic group, -OR, -CO2R/ -CONH(R*) ,
-N(R^)COR, -N(R*)S02R, -N(R^)COCH2CH2N(R*)2/ or
-N(R^)COCH2CH2CH2N{R*)2; and

(d) R^ is hydrogen or a substituted or unsubstituted
Ci-6 aliphatic, and L is -0-, -S-, or -NH-.

Representative compoiands of formula IIIc are
shown below in Table 7.

-143-

ffiu Ph

IIIc-16 IIIc-17

IIIC-19 IIIC-20

IIIC-22 IIIc-23

H

IIIC-18

Me

H

IIZc-24

-144-

H H
Ilic-25 IIIC-26

In another embodiment, this invention provides
a composition comprising a compound of formula IIIc and a
pharmaceutically acceptable carrier,
r ) Another aspect of this invention relates to a

5 method of treating or preventing an Aurora-2 -mediated
disease with an Aurora -2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
con5>ound of formula IIIc or a pharmaceutical composition
10 thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIIc or a composition comprising said
" ] 15 compound.

Another aspect of this invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

20 therapeutically effective amount of a compound of formula
IIIc or a pharmaceutical composition thereof.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,

25 which method comprises administering to the patient a

therapeutically effective amount of a compound of formula

-145-

IIlc or a pharmaceutical composition thereof. This
method is especially useful for diabetic patients.
Another method relates to inhibiting the production of
hyperphosphoiYlated Tau protein, which is useful in
5 halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for .
treating schizophrenia.

' Another aspect of this invention relates to a
10 method of inhibiting GSK-3 activity in a patient/ which
method comprises administering to the patient a compotind
of formula IIIc or a composition comprising said
compound.

Another aspect of this invention relates t-o a •

15 method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method cotiprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of foannula
IXIc or a phi-rmaceutical composition thereof.

20 Another aspect of the invention relates to

inhibiting Src activity in a patient, which method
comprises administering to the patient a compound of
formula IIIc or. a composition comprising said compound.

Another method relates to inhibiting Aurora-2,

25 GSK-3, or Src activity in a biological sample, which

method comprises contacting the biological sample with
the Aurora-2, GSK-3, or Src inhibitor of foinmila IXIc, or
a pharmaceutical composition thereof, in an amount
effective to Aurora-2, GSK-3, or Src.

30 Each of the aforementioned methods directed to

the inhibition of Aurora-2, GSK-3, or Src, or the
treatitlent of a disease alleviated thereby, is preferably

-146-

carried out with a preferred compound of formula IXIc, as
described above.

Another embodiment of this invention relates to
compounds of formula IX Jd:

5 or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:

Q' is selected from -C(R^')2-/ 1 , 2-cyclopropanediyl, 1,2-
cyclobutanediyl , or 1,3- cyclobutanediyl ;
and are independently selected from T-R^ or L-Z-R^;

10 R^ is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroarYl*
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected

15* from nitrogen, oxygen or sulfur, wherein each

sxjbstitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and eaoh
substitutable ring nitrogen of Ring D is independently
substituted by -R*;

20 T is a valence bond or a C1-4 alkylidene chain, wherein
when Q' is -C(R^')2- a methylene group of said C1-4
alkylidene chain is optionally replaced by -0-, -S-,
-N(R^)-, -co-, -CONH-, -NHCO-, -SO2-, -SO2NH-, -NHSO2-,
-C02-^ -0C(0)-, -0C(O)NH-, or -NHCO2-;

25 Z is a Ci-4 alkylidene chain;

-147-

L is -SO-, -SO2-, -N(R^)S02-, -SOsNCR^)-,

-N(R^)-, -CO-, -CO2-, "NCR^yCO-, -N(R^)C(0)0-,
-N(R^)CON(R^)-, -N(R^)S02N(R^)-, -N (R^) N (R^) - ,
-C(0)N(R^)-, -0C(0)N(R^)-, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R^)2Sa2-, -C(R^)2S02N(R^)-, -C (R^) 2N(R^) - ,
-C(R^)2N (R^) C(0)-, -C(R^)2N(R^)C(0)0-, -C (R^) =NN (R^) - ,
-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C (R^) 2N (R*^) CON (R*^) - ;

R^ and R^' are independently selected from -R, -T-W-R^, or
r2 and R^' are taken together with their intervening
atoms to form a fused, 5-8 merabered, imsatxirated or
partially xinsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
subs ti tut able ring carbon of said fused ring formed by
R^ and R^' is independently substituted by halo, 0x0,
-CN, -NO2/ -R^/ or -V-R^, and each subs ti4:ut able ring
nitrogen of said ring formed by and R^' is
independently substituted by R*;

R^ is selected from -R, -halo, -OR, -C<=0)R,- -CO2R/
-COCOR, -COCai2COR, -NO2, -CN, -S{0)R, -3(0)2R* -SR,
-N(R^)2, -CON(R^)2, -S02N(R"')2, -0C(=0)R, -N(R'')<:0R,
-N(R'')C02{Ci-€ aliphatic), -N(R*)N(R*)2/ -C=NN(R^)2,
-C=N-0R, -N(R'')C0N(R'')2, -N(r'')S02N(R'')2. -N(R*)S02R, or
-0C(=0)N{R"')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci.g
aliphatic, C^-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R^ is independently selected from -R*^, -COR*',

-CO2 (optionally substituted Ci-6 aliphatic) , -C0N(R^)2r
or -S02R^;

-148-

each is independently selected from -R, halo, -OR,
-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-K(R*)2. -CON{R*)2/ -S02N(R*)2; -OC(=0)R, -N(R^)COR,.
-N(R*) CO2 (optionally substituted Ci-e aliphatic) ,
-N{R*)N(R*)2, -C=NN<R*)2, -C=N-OR, -N(R*) CON(R*)2,
-N(R*) S02N(R*)2, -N(R*)S02R, or -OC(=0)N{R*) 2;

V is -0-, -S-, -SO-, -SO2-, -N(R®)S02-, -S02N(R*)-,
-H(R*)-, -CO-, -CO2-, -N(R*)CO-, -N(R®)C{0)0-,
-N{R«)CON(R*)-, -N (R*)S02N(R«)-, -N(R*)N (R*) - ,
-C(0)N(R^)-, -OC(0)N(R*)-, -C(R*)20-, -C{R*)2S-,
-C (R*):2SO-, -C{R*)2S02-, -C (R*) zSOaN (R*) - , -C (R*)2N(R*) - ,
-C{R*)2N(R*)C(0)-, -C{R«) aN(R«)C(0)0-, -C (R*) =NN(R*) - ,
-C{R*)=N-0-, -C(R<')2N(R*)N(R*)-, -C (R*) 2N (R*) SO2N (R*) - , or
-C (R*) 2N (R*) CON (R*) - ;

Wis -C(R*)20-, -C(R*)2S-, -C{R*)2SO-, -C(R*)2S02-,
-C(R*)2S02N(R^)-, -C(R«)2N(R*)-, -CO-, -CO2- ,
-C(R^)OC(0)-, -C(R*)OC(0)N(R«) -C{R*)2N(R*)O0-,
-C(R^)2N(R*)C(0)0-, -C(R*)=NN(R*) -, -C(R*)=N-0-,
-C (R^ ) 2N (R*) N (R^) - , -C (R*) 2N (R* ) SO2N (R*) - ,
-C(R*)2N(R^)C0N(R^) or -CON(R*)-;

each R^ is independently selected from hydrogen or an
optionally si±>stituted C^.^ aliphatic group, or two.
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;

each R*' is independently selected from hydrogen or a C1-4
aliphatic group, or two R^' on the same carbon atom are
taken together to form a 3-6 membered carbocycli<: ring,-
and

each R' is independently selected from hydrogen or an
optionally STibstituted Ci.g aliphatic group, or two R'
on the same nitrogen are taken together with the

-149-

nitrogen to form a 5-8 membered het^rocyclyl or
heteroaryl ring.

Preferred groups of formula llZd include
hydrogen,, alkyl- or dialkylamino, acetamido, or a C1.4
5 aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.

Preferred groups of formula IlXd include T-R^
or L-Z-R^ wherein T is a valence bond or a methylene, L is
.0-, -S-, or -N(R*)-, -C(R^)20-, -CO- and R^ is -R,

10 -N(R*)2/ or -OR. Examples of preferred R^ groups include
2-pyridyl, 4-pyridyl, pyrrplidinyl , piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxyniethyl or

15 methoxyethyl , alkyl- or dialkylamino such as ethylamino
or dimethylamino, alkyl- or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally stabstltuted
phenyl such as phenyl or halo-sxibstituted phenyl.

The R^ and R^' groups of formula Xlld may be

20 taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6 -membered carbocyclo ring.
These are exemplified in the following formula llld

25 compoimds having a pyrazole -containing bicyclic ring
system:

-150-

Pref erred substituents on the R^/R^' fused ring
of formula Hid include one or more of the following:
-halo, -N{R^)2. -Ci-4 alkyl, -C1.4 haloalkyl, -0(Ci-4
5 allcyl) / -C02(Ci-4 alkyl) , -S02(Ci-4 alkyl) , -SO2NH2/

-0C{0)NH2, -NH2S02(Ci-4 alkyl) , -NHC(O) (C1.4 alkyl) ,
-C(0)NH2, and -CO (C1.4 alkyl) , wherein the (C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl.
10 When the pyrazole ring system of formula Illd

O is monocyclic, preferred R^ groups include hydrogen or a

substituted or unsubstituted group selected from aryl,
heteroaryl, or a Ci-6 aliphatic group. Examples of such
preferred R^ groups include H, methyl, ethyl, propyl, ,
15 cyclopropyl, i -propyl, cyclopentyl, hydroxypropyl ,

methoxypropyi, and benzyloxypropyl . A preferred R^' group
is hydrogen.

When Ring D of formula Illd is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
20 pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula Illd is bicyclic,
) preferred bicyclic Ring D groups include naphthyl,

tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b] f uryl ,
2 5 benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl ,
1, 8-naphthyridinyl and isoquinolinyl .

On Ring D of formula Illd, preferred T-R^ or
V-Z-R^ substituents include -halo, -CN, -NO2, -N(R^)2/
30 optionally substituted Ci.e aliphatic group, -OR, -C(0)R,
-CO2R, -CONH(R^), -N(R^)COR, -N(R^)C02R, -^02N(R*)2,
-N(R*)S02R, -N{R^)COCH2N(R^)2/ -N (R^) COCH2CH2N (R^) 2/ and ,
-N{R^)COCH2CH2CH2N(R*)2f wherein R is selected from

-151-

hydrogen, Ci-s aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred substituents include -Cl, -Br, -F, -CN,
-CF3, -COOH, -CONHMe, -CONHEt, -NH2/ -NHAc , -NHSOzMe ,
-NHS02Et, -NHSO2 (n- propyl) , -NHSO2 (isopropyl) , -NHCOEt,
-NHCOCH2NHCH3, -NHC0Cai2N (COzt-Bu) Caia , -NHC0Cai2N (CH3) 2/
-NHCOCH2CH2N(CH3)2, -NHCOCH2CH2CH2N (CH3) 2#

-NHCO ( cyclopropyl ) , -NHCO { isobutyl ) , -NHCOCH2 (morpholin-4 -
yl) , -NHCX>CH2CH2{morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-
4-.yl), -NHCOaCt-butyl) , -NH(Ci-4 aliphatic) such as -NHMe,"
-N{Cx-4 aliphatic) 2 such as -NMe2, OH, -o(Ci-4 aliphatic)
such as -OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and -C02(Ci-4
aliphatic) .

Preferred Q' groups of formula Zlld include
-C(R^')2- or 1,2-cyclopropanediyl, wherein each R*' is
independently selected from hydrogen or methyl. A more
preferred Q' group is -CH2-.

Preferred formula Zlld compounds have on3 or
more, and more preferably all, of the features selected
from the group consisting of:

(a) R^ is hydrogen, alkyl- or dialkylamino,
acetamido, or a C1-4 aliphatic group;

(b) R^ is T-R^ or L-Z-R^, wherein T is a valence bond
or a methylene, and R^ is -R, -N(R^)2/ or -OR;

(c) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit and wherein said methylene iinit
is optionally replaced by -0-, -NH-, or -S-;

(d) Ring D is a 5-7 membered monocyclic or an 8-10
. membered bicyolic aryl or heteroaryl ring; and

(e) R^ is -R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are taken together to form an optionally
siobstituted benzo ring-

-152-

More preferred compoiands of formula Illd have
one or more> and more preferably all, of the features
selected from the group consisting of:

(a) is T-R^ or L-Z-R^ wherein' T is a valence bond
• or a methylene and R^ is selected from -R, -OR,

or -N{R*)2/ wherein R is; selected from hydrogen,

aliphatic, or 5-6 membered heterocyclyl ,
phenyl, or 5-6 membered heteroaryl;

(b) R^ is T- (Ring D) , wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;

(d) R^ is -R and R^' is hydrogen, wherein R is ...
seilected from hydrogen, Ci-s aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;

(e) L is -0-, -S-, or -N(R*)-; and

(f) Q' is -C(R^')2- or 1, 2-cyclopropanediyl, wherein
each R^' is independently selected from hydrogen
or methyl.

Even more preferred compounds of formula Zlld
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R"" is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido;

(b) R^ is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl , ethyl , cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl- or dialkylamino, alkyl- or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl ;

-153-

(c) is (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from -halo, -CN,
-NO2/ -N(R*)2> optionally substituted Ci-e
aliphatic group, -OR, -CO2R, -CONH(R*),
-N{R*)COR, -N(R*)S02R, -N(R^) COCH2CH2N(R*) 2, or -
-N (R^) COCH2CH2CH2N (R*) 2 ;

(d) R^ is hydrogen or a substituted or unsubctituted
Ci-6 aliphatic; and L is -0-, -S-, or -13H-; and

(e) Q' is -CH2-.

Representative compounds of formula IXZd are
shown below in Table 8.

Table 8.

IIId-1 IIId-2 IIId-3

IIId-4 IIId-5 IIId-6

-154^

-155-

IIId-19 IIId-20 IIId-21

IIId-22 IIId-23 IIId-24

In another embodiment, this invention provides
a composition comprising a compound of formula Zlld and a
pharmaceutically acceptable carrier-

Another aspect of this invention relates to a
method' of treating or preventing an Aurora -2 -mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula XXId or a pharmaceutical composition
thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula Illd or a composition comprising said
compound.

Another aspect of this invention relat-es to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK- 3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

-156-

therapeutically effective amount of a compoxand of formula
IZId or a pharmaceutical composition thereof.

One iaspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
5 blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
Zlld or a pharmaceutical composition thereof- This
method is especially useful for disO^etic patients.

10 Another method relates to inhibiting the production of
CD hyperphosphorylated Tau protein, which is useful in

halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for

15 treating schizophrenia.

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula Illd or a composition comprising said

20 compound.

Another method relates to inhibiting Aurora- 2
or .GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora- 2 or GSK-3 inhibitor of formula Illd, or a

25 pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to
the inhibition of Aurora- 2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out

30 with a preferred compound of formula Xlld, as described
above .

Another embodiment of this invention relates to
con^oiinds of formula IVa :

-157-

iva

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:

is nitrogen or C-R® and 7? is nitrogen or CH, wherein

one of or Z^ is nitrogen;

and R^ are independently selected from T-R^ or L-Z-R^,
or R^ and R^ are taken together with their intervening
atoms to form a fused/ unsaturated or partially
imsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by R^ and R^ is independently substituted
by oxo, T-R^, or L-Z-R^, and each substitutable ring
nitrogen of said ring formed by R* and R^ is
independently svibstituted by R*;
R^ is T- (Ring D> ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and each
s\jJDStitutable ring nitrogen of Ring D is independently
substituted by -R*;

-158-

T is a valence bond or a C1-4 alkylidene chain;
Z is a Ci-4 alkylidene chain;

L is -S-, -SO-, -SO2-, -N(R^)S02-, -SOzNCR^)-,

.N(R^)-/ -CO-, -C02-r -N(R^)CO-, -=N(R^)C(0)0-,
-N{R^)CON {R^)-, -N(R^)S02N (R^) -, -N(R^)N(R^)
-C(0)N(R^)-, -OC(0)N(R«)-/ -C(R*^)20-, -C(R^)2S-,
-C(R^)2SO-^ -C(R^)2S02-, -C(R^)2S02N(R^)-, -C(R^)2N(R^)-,
-C(R^)2N(R^)C(0)-, -C(R«)2N(R^)C(0)0-, -C (R^) =NN (R^) - ,
-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C{R^)2N(R^) S02N(R^) or
-C (R^) 2N (R^) CON (R^) - ;

R^ and R^'. are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially \msaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfiur, wherein each
substitutable ring carbon of said fused ring formed by
R^ and R^' is independently substituted by halo, 0x0,
-CN, -NO2/ -R"'/ or -V-R^, and each substitutable ring
nitrogen of said ring formed by R^ and R^' is
independently substituted by R*;

R^ is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -S(0)2R/ -SR,
-N{R'*)2/ -C0N(R"')2, -S02N(R'')2, -0C<=0)R, -N(R^)C0R,
-N(R'')C02{Ci.6 aliphatic) , -N (R*)N (R^) 2, -C=NN(R*)2/
-C=N-0R, -N(R'')CON(r'')2/ -N(R'')S02N(r'')2/ -N{R^)S02R, or

-oc(=o)n(r'')2;
each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-e
aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ;

-159-

each R*- is independently selected from -r', -COR',

-CO2 (optionally siibstituted Ci-s aliphatic) , -CON(r')2/
or -SQzB? ;

each R* is independently selected from -R, halo, -OR,
-C(=0)R, -COaR,- -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -C0N(R*)2/ -S02N(R*)2» -OC(=0)R, -N{R*)COR,
-N{R*)C02 (optionally siabstituted Ci-s aliphatic),
-N(R*)N(R*)2, -C=NN(R*)2, -C=N-OR, -N (R*) GON(R*) 2,
-N(R*)S02N(R*)2, -N(R*)SOaR, or -OC(=0)N(R*) 2;

V is -0-, -S-, -SO-, -SO2-, -N(R*)S02-, -S02N(R*)-,
-N(R«)-, -CO-, -CO2-, -N(R*)CO-, -N(R*)C(0)0-,
-N (R«) CON (R*) - , -N (R«) SO2N (R*) - , -N(R«) N<R*) - ,
-C(0)N(R*)-, -OC{0)N(R*)-, -C(R*)20-, -C(R*)2S-,
-C (R*) 2SO- , -C (R*) 2SO2- , -C (R*) 2SO2N (R*> - , -C (R*) 2N (R*) - ,
-C(R*)2N(R*)C{0)-, -C(R«)2N(R*)C(0)0-, -C (R*) -NN (R^) - ,
-C(R*)=N-0-, -C(R«)2N(R*')N(R«)-, -C(R*)2N(R^)S02N(R*) -,
-C (R*) 2N (R*) CON (R*) - ;

W is -C(R*)20-, -C(R*)2S-, -C(R*)2SO-, -C(R«)aS02-,
-C(R*)2S02N(R*) -, -C(R*)2N(R®)-, -CO-, -CO2-,
-C(R*)OC(0)-, -C(R*)OC(0)N(R"')-, -C (R*).2N (R*) CO- ,
-C(R^)2N(R^)C(0)0-, -C(R*)=NN(R*)-, -C(R*)=N-0-,
-C(R^)2N(R*)N{R«)-, -C(R*)2N(R*)S02N{R*)-,
-C(R*)2N(R*)CON(R^) -, or -CON(R*)-;

each R* is independently selected from hydrogen or an
optionally siibstituted C1-4 aliphatic group, or two R*
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;

each r'' is independently selected from hydrogen or an
optionally substituted Ci-e aliphatic group, or two r'^
on the same nitrogen are taken together with the
nitrogen to torm a 5-8 membered heterocyclyl or
heteroaryl ring; and

-160-

R« is selected from -R, halo, -OR, -C(=0)R, -CO2R, -COGOR,

-NO2, -casr, -s(o)R, -SO2R, -sr, -n{r*)2/ -con(r'*)2,

-S02N(R*)2/ -OC(=0)R, -N(R*)C0R, -N (R*) CO2 (optionally
substituted C1.6 aliphatic) , -N(R*)N(R*)2, -C=NN(R*)2,
-CoN-OR, -N (R*) CX>N (R*) 2> - -N<R^) SO2N (R*) 2 , "N (R*) SO2R, or
-0C(=0)N(R*)2.

Preferred rings formed by R* and R^ of formula
IVa include a 5-/6-, or 7-membered unsaturated or
partially unsaturated ring having 0-2 heteroatoms,
wherein said RVR^ ring is optionally substituted. Iliis .
provides a bicydic ring system containing a pyridine
ring. Preferred pyridine ring systems of formula XVa are
shovna below.

IVa-A iVa-B IVa-C

IVa-D IVa-E IVa-P

HN^ HN-^ HN-^

exit, ott^

IVa-J IVa-K IVa-L

-161-

IVa-W

More preferred pyridine ring systems of formula
IVa include IVa-A, IVa-B, IVa-D, IVa-E, IVa-J, IVa-P, and
IVa-V, most preferably IVa-A, IVa-B, IVa-D, IVa-E, and
IVa- J. Even more preferred pyridine ring systems of
5 formula IVa are those described above, wherein is
nitrogen and is CH.

Preferred groups of formula IVa include
hydrogen, alkyl- or dialkylamino, acetamido, or a'Ci-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
10 isopropyl •

Preferred groups of formula IVa include T-R^
or L-Z-R^ wherein T is a valence bond or a methylene, L is

or -N(R^)-, -C(R^)20-, -CO- and R^ is -R,
-N(R^)2/ or -OR- Examples of preferred R^ groups include

15 2-pyridyl, 4-pyridyl, pyrrol idinyl , piperidinyl,

morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino such as
me thoxye thy 1 amino, alkoxyalkyl such as methoxymethyl or
methoxyethyl , alkyl- or dialkylamino such as ethylamino

20 or dimethylamino, alkyl- or dialkylaminoalkoxy such as*

-162-

dimethylaminopropyloxy, acetamido, optionally sxibstituted
phenyl such as phenyl or halo-siibstituted phenyl.

The ring formed when the and groups of
formula IVa are taken together may be siibstituted or
5 iinsubstituted. Suitable- substituents -include —R, halo,

-0{CH2)2-4-N(R^)2/ -0{CH2)2-4-R, -OR, -N(R*)-(CH2)2-4-N(R*)2/
--N(R*)-(CH2)2-4-R* -C(=0)R, -CO2R, -COCOR, -NO2, -Ca^I,
-S(0)R, -SO2R, -SR, -N(R^)2/ -CON(R*)2/ -S02N(R*)2,
-OC(=0)R, -N(R*)COR, -N(R*)C02 (optionally substituted Ci-e
10 aliphatic), -N(R*)N(R*)2> -C=NN(R*)2. -C=N-OR,
O -N(R*)C0N(R*)2. -N(R*)S02N(R*)2. -N(R*)S02R/ or

-0C(«0)N{R*)2/ R and R* are as defined ^ove. Preferred
R^/R^ ring sxabstituents include -halo, -R, -OR, -COR,
-COaRr -CON(R*)2. "CN, -O (CH2) 2-4-N (R*) 2/ -O (CH2) 2.4-R, . -NO2
15 -N(R*>2, -NR^COR, -NR^S02R, -S02Nm*)2 wherein R is hydrogen
or an optionally substituted Ci-e aliphatic group.

The R^ and R^' groups of formula IVa may be
taken together to form a fused ring, thus providing a
bicyolic ring system containing a pyrazole ring.
20 Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
C^j . These are exemplified in the following f-ormula IVa

compounds having a pyrazole -containing bi<rjrclic ring
system:

-163-

Preferred substituents on the R^/R^' fused ring
of formula IVa include one or more of the following:
-halo, -N (R*) 2/ -C1.4 alkyl, -C1-4 haloalkyl , -NO2, -O (Cx-4
alkyl) , -C02(Ci-4 alkyl) , -CN, -SOaCCi.* alkyl) , -SO2NH2/
5 -0C(0)NH2. -NH2S02(Ci-4 alkyl) , -NHC<0) (C1.4 alkyl) ,

-C(0)NH2, and -CO (C1-4 alkyl) , wherein the (C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl.

When the pyrazole ring system of formula IVa is

10 monocyclic, preferred R^ groups include hydrogen or a
substituted or unsiobstituted group selected from aryl,
heteroaryl, or a Ci-g aliphatic group. Examples of such
preferred R^ groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i -propyl, cyclopentyl, hydroxypropyl ,

15 methoxypropyl., and benzyloxypropyl . A preferred R^' group
is hydrogen.

When Ring D of formula IVa is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, auad pyrazinyl.

20 When Ring D of formula IVa is bicyclid,

preferred bi cyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indsmyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [bj f uryl ,
benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

25 cinnolinyl, phthalazinyl , quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl .

On Ring D of formula IVa, preferred T-R^ or V-Z-
R^ substituents include -halo, -CN, -NO2, -N(R*)2/
optionally sxibstituted Ci-g aliphatic group, -OR, -C(0)R,

30 -CO2R, -COKH(R^), -N(R^)COR, -N(R^)<!02R, -S02N(R^)2,

-N(R^)S02R, -N(R^)COCH2N(R*)2/ -N (R^) GOCH2CH2N (R*) 2, and
-N(R^)COCH2CH2CH2N{R*)2/ wherein R is selected from
hydrogen, Ci-e aliphatic, phenyl, a 5-6 membered

-164-

heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred svibstituents include -CI, -Br, -F, -CN,
-CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSOaMe,
-NHSO2E t , -NHSO2 (n-propyl ) , -NHSO2 ( isopropyl ) , -NHCOEt ,
-NHCOCHzNHCHsr -NHCOCH2N(G02t-Bu)CH3, --NHCOCH2N(CH3)2,
-NHCOai2CH2N(CH3)2# -NHCOCH2CH2CH2N( 013)2,

-NHCO ( cyclopropyl ) , -NHCO ( isobutyl ) , -NHCOCH2 {morpholin-4 -
yl ) , -NHCOCH2CH2 (morpholin-4 -yl ) , -NHGOCH2CH2CH2 (morpholin-
4-yl) , -NHC02(t-butyl) , -NH (Ci.4 aliphatic) such as -NHMe,
-N(Ci.4 aliphatic) 2 such as -NMe2/ OH, -0(01-4 aliphatic)
such as -OMe, C1-4 aliphatic such as methyl^ ethyl,
cyclopropyl, isopropyl, or t -butyl, and -CO2 (C1-4

aliphatic) .

Prefezxed groups of formula IVa, when
present, include R, OR, and N(R*)2. Examples of prefeirred
R® include methyl, ethyl, NH2, NH2CH2CH2NH, NCCHa) 2CH2CH2NH,
N(CH3)2CH2CH20, (piperidin-l-yl)CH2CH20, and NH2CH2CH2O.

Preferred formula IVa compoimds have one or
more, and more preferably all, of tlie features selected
from the group consisting of:

(a) R^ is hydrogen, alkyl- or dialkylamino,

acetamido, or a C1.4 aliphatic group and R^ is
T-R^ or L-Z-R^, wherein T is a valence bond or a
methylene and R^ is -R, -N(R*)2, or -OR; or R^" and
R^ are taken together with their intervening
atoms to form a fused, unsaturated or partially
iinsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein ^ach substitutaible ring carbon
of said fused ring formed by Ri* and R^ is
independently substituted by 0x0, T-R^, or L-Z-
R^, and each substitutable ring nitrogen of said

-165-

ring formed by R* and is independently
sxibstituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(c) Ring D -is a 5-7 inembered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and

(d) R^ is -R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are tcJcen together to form an optionally
substituted benzo ring.

More preferred compoxinds of formula IVa have
one or more, and more preferably all, of the features
selected from the group- consisting of:

(a) R^ is T-R^ or L-Z-R^ wherein T is a valence bond
or a methylene and R^ is selected from -R, -OR,
or -N(R^)2r wherein R is selected from hydrogen,
Ci-e aliphatic, or 5-6 membered heterocyclyl ,
phenyl, or 5-6 membered heteroaryl; or R* and R^
are taken together with their intervening atoms

^ to ±orm a benzo, pyrido, cyclc^nto, cyclohexo,
cyclohepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by R"" and R^ is independently
substituted by oxo, T-R^, or L-Z-R^, and each
substitutable ring nitrogen of said ring formed
by 'S^ and R^ is independently substituted by R^;

(b) R^ is T- (Ring D) , wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-
10 membered bicyclic aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-g aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;6u:id

-166-

(d) is selected from -R, -halo, -OR, or -N(R^)2/
wherein R is selected from hydrogen, Ci-e
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R*)-.

Even more preferred confounds of formula IVa
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) R* is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or acetamido
and R^ is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkyl amino,
alkoxyalkyl, alkyl- or dialkylamino, alkyl- or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl ; or R* and

are taken together with their intervening
atoms to form a benzo, pyrido, piper idino, or
cyclohexo ring, wherein said ring is optionally
substituted with -halo, -R, -OR, -COR, -CO2R,-
-CON(R^)2/ -CN, -0(CH2)2-4-N{R^)2. -O {GH2) 2-4-R/ -NO2
-N(R^)2, -NR^COR, -NR^SOzR, or -S02N(R^)2/ wherein
R is hydrogen or an optionally substituted Ci-g
aliphatic group;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl ring
optionally substituted with one or two groups
selected from -halo, -CN, -NO2/ -N{R*)2#
optionally substituted C1.6 aliphatic, -OR,
-C(0)R, -CO2R, -CONH{R*), -N(R*)COR, -N(R*)C02R.
-S02N(R*)2, -N(R*)S02R, -» (R^) COCH2N (R^) 2/
-N(R^)C0CH2CH2N(R*)2r or -N (R^) COCH2CH2CH2N (R*) 2;

-167-

(c) is hydrogen or a siibstituted or unsxibstituted
» group selected from aryl, heteroaryl, or a Ci-e

aliphatic group, and R^' . is hydrogen; and

(d) R^ is selected from -R, -OR, or -N(R*)2, wherein
R is selected from hydrogen, Ci-c aliphatic, 5-6
membered heterocyclyl , phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R*)2r optionally substituted C1.6 aliphatic
group, -OR, -C(0)R, -CO2R, -CONH(R*) , -N{R*)COR,
-N(R*)C02R/ -S02N(R*)2# -N(R*)S02R,
-N(R^)C0CH2N(R*)2/ -N{R^)COCH2CH2N(R*)2* or
-N(R^)C0CH2CH2CH2N(R*)2/ wherein R is selected
from hydrogen, Cx-g aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

Representative compounds of formula IVa are
shown below in Table 9 •

Table 9.

Me

HN'^N H
IVa-l

4

-168-

IVa-10 rva-11 IVa-12

In emother embodiment, this invention provides
a coioposition comprising a compovind of formula IVa and a
pharmaceutically acceptable carrier.

Another aspect of this invention relates to a
5 method of treating or preventing an Aurora -2 -mediated
disease with an Atirora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
con?>ound of formula IVa or a pharmaceutical con5>Qsition

10 thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a

-169-

compound of formula iva or a coinposit:ion comprising said
compound •

Another aspect of this invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
5 with a GSK- 3 inhibitor, which method comprises

administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
XVa or a pharmaceutical composition thereof.

One aspect of this invention relates to a

10 method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IVa or a pharmaceutical composition thereof. This method

15 is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the

2t) phosphorylation of P-catenin, which is useful for
treating schizophrenia.

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compovmd

25 of formula IVa or a composition comprising said compound.

Another method relates to inhibiting Aurora- 2
or GSK-3 activity in a biological sample, whi-ch method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IVa, or a

30 pharroaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to
the inhibition of Aurora-2 or <3SK-3, or the treatment of

-170-

a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IVa, as described
above.

Another embodiment of this invention relates to
5 compounds of formula IVb:

ivb

10 or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:

is nitrogen or C-R* and is nitrogen or CH, wherein
one of Z^ or is nitrogen;

and R^ are independently selected from T-R^ or L-Z-R^.

15 or R"" and R^ are taken together with their intervening

atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused

20 ring, formed by R^" and R^ is independently substituted

by oxo, T-R^, or L-Z-R^, and each substitutable ring
nitrogen of said ring formed by R* and R^ is
independently sxibstituted by R*;
R^ is T- (Ring D) ;

25 Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaiyl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected

-171-

from nitrogen, oxygen or sulfur, wherein each
subs ti tut able ring carbon of Ring D is independently
sxibstituted by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
substituted by -R^;

T is a valence bond or a C1.4 alkylidene chain;

Z is a C1.4 alkylidene chain;

L is -SO-/-SO2-/ -N(R^)S02-, -S02N(R^)-,

-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C{0)0-,
-N(R^)CON{R^)-, -N(R^)S02N(R^)-, -N (R^)N(R^)
-C(0)N(R^)-, -OC(0)N(R^) -C{R^)20-, -C{R^)2S-,
-C{R^)2S0-, -C(R^)2S02-, -C(R^)2S02N(R^)-, .C(R^)2N(R^)
-C<R^)2N(R^)C(0)-. -C(R*)2N(R^)C(0)0-, -C(R^) =NN(R^)
-C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C(R^)2N(R^)CON(R^)-;

R^ and R^' are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 merobered, unsaturated or
partially xinsatvxated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur^ wherein ^ach
substitutsJDle ring carbon of said fused ring formed by
R^ and R^' is independently substituted by halo, 0x0,
-CN, -NO2, -R^/ or -V-R^, and each substitu1:able ring
nitrogen of said ring formed by R^ and R^' is
independently substituted by R*;

R^ is selected from -R, -halo, -OR, -C(=b)R, -CO2R,
-COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -S{0)2R/ -SR,
-N(R^)2, -C0N(R'')2, -S02N{R'')2/ -0C(=0)R, -N(R'')G0R,
-N(R^)C02(Ci.6 aliphatic) , -N{R^)N(R^) 2/ -C=NN(R^)2/
-C=N-OR, -N(R'')CON(R"')2r -N (R'')«02N (R'') 2, -N{R*)S02R, or
-0C(=0)N(R'')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-e

-172-

aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R* is independently selected from -r', -COR',

-CO2 (optionally • siabstituted Ci-e aliphatic) , -CON (R') 2/
or -SO2R';

each R^ is independently selected from -R, halo, -OR,
-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -CX)N(R*)2, -S02N(R*)2, -OC(=0)R, -N(R*)COR,
-N{R'*)C02 (optionally siibstituted Ci_6 aliphatic) ,
-N(R*)N(R*)2, -C=NN(R*)2, -C=N-OR, -N (R*) CON (R*) 2,
-N(R*)S02N(R*)2, -N(R*)S02R, or -OC(=b)N(R*)2;

V is -0-, -S-, -SO-, -SO2-, -N(R®)S02-, -S02N(R*)-,
-N(R^)-, -CO-, -CO2-, -N(R*)CO-, -N(R*)C(0)0-,
-N (R«) CON (R«) - , -N (R*) SO2N (R«) - , -N (R*) N (R«) - ,
-C(0)N(R®)-, -OC(0)N(R*)-, -C(R*)20^, -C(R*)2S-,
-C(R«)2SO-, -C(R«)2S02-, -G(R*)2S02N(R*)-, -C (R^) 2N(R*) - ,
-C(R«)2N(R^)C (0)-, -C{R«)2N(R*)C(0)0-, -C (R*) =NN (R") - ,
-C(R«)=N-0-, -C(R«)2N{R*)N(R^)-, -C(R«)2N(R*)S02N'R*)-,
-C(R*)2N(R^)C0N(R*)-;

W is -C(R^)20-, -C(R*)2S-, -C(R^)2S0-, -C(R*)2S02-,
-C(R^)2S02N(R^)-, -C(R®)2N(R^) -co-, -CO2-,
-C(R*)0C(0)-, -C(R^)0C(0)N(R^) -, -C(R^)2N(R*)C0-,
-C(R*)2N(R^)C{0)0-, -C(R^)=NN(R^) rC(R^)=N-0-,
-C(R*)2N(R^)N(R«) -C(R^)2N(R^)S02N(R*)-,
-C(R^)2N(R^)C0N(R^) -, or -CON(R*)-;

each R^ is independently selected from hydrogen or an
optionally siabstituted C1-4 aliphatic group, or two R*
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;

each r' is independently selected from hydrogen or an
optionally substituted Ci-s aliphatic group, or two r'

-173-

on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and

is selected from -R, halo,. -OR, -C{=0)R, -CO2R. -COCOR,
-NO2/ -CN, -S(0)R, -SOsR, -SR, -N(R*)2/ -CON{R*)2r
.-S02N(R*)2, -OC(=0)R, -N(R*)COR, -N (R*) CO2 (optionally
svibstituted C1.6 aliphatic) , -N(R*)N(R*)2# -C=NN(R*)2/
.C=N-OR, -N{R*)CON{R*)2, -N (R*) SO2N (R*) 2, -N(R*)S02R, or

-0C(=0)N(R*)2- •

Preferred rings formed by R* and R^ of formula
rvb include a 5-, 6-, or 7 -membered unsaturated or
partially unsaturated ring having 0-2 heteroatoms, ,
wherein said rVR^ ring is optionally substituted. This
provides a bicyclic ring system containing a pyrimidine
ring. Preferred pyrimidine ring systems of formula IVb
are shown below.

IVb-D IVb-E IVb-P

-174-

rvb-w

More preferred pyrimidine ring systems of
formula IVb include IVb-A, IVb-B, IVb-D, IVb-E, IVb-J/
IVb-P, cuid rvb-V, most preferably IVb-A, IVb-B, IVb-D,
rvb-B, and IVb- J. Even more preferred pyridine ring
systems of formula IVb are those described above, wherein
is nitrogen and xs CH.

Preferred groups of formula IVb include
hydrogen, alkyl- or dialkylamino , acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclc^ropyl, or
isopropyl •

Preferred groups of f oirmula rvb include T-R^
or L-Z-R^ wherein T is a valence bond or a methylene, Ii is

or -N(R^)-, -C(R^)20-, -CO- and R^ is -R,
-N(R^)2, or -OR. Examples of preferred R^ groups include

-175-

2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl* piperazinyl/ methiyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino such as
methoxyethyiamino, alkoxyalkyl such as methoxymethyl or
5 methoxyethyl, alkyl- or dialkylamino such as ethylamino
or dimethylamino, allcyl- or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-sidjstituted phenyl.

Hxe ring formed when the R* and groups of
10 formula TVba are taken together may be substituted or
unsxabstituted. Suitable substituents include -R, halo,

-0(C3l2)2-4-N(R*)2, -0(C2l2)2.4-R, -OR, -N(R*)-(CH2)2-4-N(R*)2/

-N(R*)-(CH2)2-4-R, -C(=0)R, -CO2R, -COCOR, -NO2, -CN,
-S(0)R, -SO2R, -SR, -N(R*)2, -CON(R*)2, -S02N(R*)2,

15 -OC(=0)R, -N{R*)COR, -N{R*) CO2 (optionally s\abstituted Cx-s
aliphatic), -N(R*)N(R'»)2, -C=NN(R*)2, -C=N-OR,
-N(R*)CON(R*)2, -N(R*)S02N(R*)2/ -N(R*)S02R, or
-0C(=0)N(R*)2# R and R* are as defined above. Preferred
R*/R^ ring svibstituents include -halo, -R, -OR, -COR,

20 -CO2R, -C0N(R*)2, -CN, -0(Cai2)2-4-N{R*)2/ -O (CH2) 2-4-R/ . -NO2
-N(R*)2, -NR*COR, -NR^SOaR, -S02N(R*)2 wherein R is hydrogen
or an optionally substituted Ci-e aliphatic group.

The and R^' groups of formula IVb may be
taken together to form a fused ring, thus providing a

25 bicyclic ring system containing a pyrazole ring.

Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-merabered carbocyclo ring.
These are exemplified in the following formula IVb
coii5>ounds having a pyrazole -containing bicyclic ring

30 system:

-176-

Preferred substituents on the R^/R^' fused ring
of formula I Vb include one or more of the following:
-halo, -N(R^)2. -Ci_4 alkyl, -C1.4 haloalkyl, -0(Ci-4
alkyl), -C02(Ci-4 alkyl) , -CN, -SO2 {C1-4 alkyl) , -SO2NH2,
5 -0C(0>NH2/ -NH2S02(Ci.4 alkyl) , -NHC{0) (C1-4 alkyl) ,

-C(0)NH2, and -CO(Ci.4 alkyl) , wherein the (C1.4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (Ci-4 alkyl) group is methyl-

When the pyrazole ring system of formula IVb is

10 monocyclic, preferred R^ groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a Ci-e aliphatic group. Exait^les of such
preferred R^ groups include hydrogen, methyl, ethyl,
propyl, , cyclopropyl, i -propyl, cyclopentyl,

15 hydroxypropyl, methoxypropyl , and benzyloxypropyl . A
preferred R^' group is hydrogen^

When Ring D of formula IVb is monocyclic,
preferred Ring D groups include phenyl ^ pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

20 When Ring D of f cannula IVb is bicyclic,

preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl , indanyl, benzimidazolyl , quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b] f uryl ,
benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

25 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl .

-177-

On Ring D of formula IVb, preferred T-R^ or
V-Z-R^ substituents include -halo, -CN, -NO2/ -N(R^)2/
optionally substituted Ci-e aliphatic group, -OR, -C(0)R,
-CO2R, -CONH(R^), -N(R^)COR, -N(R^)C02R, -S02N(R^)2,
5 -N{R*)S02R/ -N(R^)COCH2N(R^)2, -N(R^) COCH2CH2N(R^)2, and
-N(R^) COC3i2CH2CH2N(R^)2/ wherein R is selected from
hydrogen, Ci-6 aliphatic, phenyl, a 5-6 menibered
heteroairyl ring, or a 5-6 metnbered heterocyclic ring.
More preferred R^ substituents include -Cl, -Br, -F, -CN,
10 -CF3, -COOH, -COlslHMe, -CONHEt, -NH2/ -NHAc, -NHSOzMe,

-15HS02Et , -NHSO2 (n-propyl) , -NHSO2 ( isopropyl) , -NHCOEt ,
-NHCOCH2NHCH3, -NHCOCH2N(C02t-Bu)CH3/ -NHCOCH2N(CH3) 2,
-NHCOCH2CH2N (CH3 ) 2 , -NHCOCH2CH2CH2N (CH3 ) 2 ,

-NHCO ( cyclopropyl ) , -NHCO ( isobutyl ) , -NHCOCH2 (tnprpholin-4 -
15 yl) , -NHCOC^^2C3^2(morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholin-
4-yl) , -NHCO2 (t -butyl ) , -NH(Ci.4 aliphatic) such as -NHMe,
-N(Ci-4 aliphatic) 2 such as -NMe2, OH, -0(Ci-4 aliphatic:)
such as -OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or trbutyl, and -C02(Ci.4
20 aliphatic) .

Preferred R® groups of formula IVb, when
present, include R, OR, and N(R^)2. Examples of preferred
R® include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH,
N(CH3)2CH2CH20, (piperidin-l-yDCHzCHzO, and NH2CH2ai20.
25 Preferred formula IVb compounds have one or

more, and more preferably all, of the features selected
from the group consisting of:

(a) R^ is hydrogen, alkyl- or dialkylamino,

acetamido, or a aliphatic group and R^ is
3 0 T-R^ or L-Z-R^, wherein T is a valence bond or a

methylene and R^ is -R, -N{R*)2, or -OR; or R* and
R^ are taken together with their intervening
atoms to form a fused, unsaturated or partially

• f

-178-

unsaturated, 5-6 meinbered ring having 0-2
heteroatoms selected from oxygen, sul'fur, or
nitrogen, wherein each substitutable ring carbon
of said fused ring formed by and is
5 • independently substituted by oxo, T-R^-, or L-Z-

R^, and each substitutable ring nitrogen of said
ring formed by R"^ and R^ is independently
substituted by R*;
(b) R^ is T- (Ring D) , wherein T is a valence bond or
10 a methylene xinit;

(3 (c) Ring D is a 5-7 membered monocyclic or an 8-10

membered bicyclic aryl or heteroaryl ring; arid
(d) R^ is -R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are taken together to form an optionally
15 substituted benzo ring.

More preferred compoxinds of formula IVb have
one or more, and more preferably all, of the features
selected from the group consisting of:

(a) R^ is T-R^ or L-Z-R^ wherein T is a valence bond
20 or a methylene and R'^ is selected from -R, -OR,

or -N(R*)2/ wherein R is selected from hydrogen,
4 ) Ci-e aliphatic, or 5-6 membered heterocyclyl ,

phenyl, or 5-6 membered heteroaryl; or R* and R^
are taken together with their intervening atoms
25 to form a benzo, pyrido, cyclopento, cyclohexo,

cyclohepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by R"^ and R^ is independently
sxibstituted by oxo, T-R^, or L-Z-R^, and each
30 substitutable ring nitrogen of said ring formed

by R"^ and R^ is independently substituted by R*;

-179-

(b) is T- (Ring D) , wherein T is a valence bond,
and Ring D is a 5-6 metnbered monocyclic or an 8-
10 membered bicyclic aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-g aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(d) R^ is selected from -R, -halo, -OR, or -N{R*)2/
wherein R is selected from hydrogen, Ci-s
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,

: or -N{R^)-.

Even more preferred compounds of formula XVb
have one or more, and more preferably all, of the
features selected from the group consisting of :
(a) R'' is hydrogen methyl, ethyl, propyl,

cyclopropyl, isopropyl, methylamino or acetamido
and R^ is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl , piperidiryl , morpholinyl ,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkyl amino,
alkoxyalkyl, alkyl- or dialkylamino, alkyl- or
dialkylaminoalkoxy , acetamido , optionally
substituted phenyl, or methoxymethyl ; or R* and
R^ are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with -halo, -R, -OR, -COR, -CO2R,
-C0N(R^)2, -CN, -0(CH2)2-4-N(R^)2/ -O (CH2) 2-4-R, -NO2
-N{R^)2/ -NR^COR, -NR^S02R, or -S02N(R*)2, wherein
R is hydrogen or an optionally substituted Ci-6
aliphatic group;

-180-

(b) is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 mexnbered aryl or heteroaryl ring
optionally sxabstituted with one or two groups
selected from -halo, -CN, -NO2/ -N{R*)2/

- optionally substituted d-s aliphatic, -OR,

-C(0)R, -CO2R/ -CONH(R*)> -N(R*)COR, -N{R*)C02R/
-S02N(R*)2/ -N(R*)S02R. -N(R^) COCH2N(R*) 2/
-N(R^)COCH2CH2N(R*)2. or -N (R^) COCHaCHsCHaNCR^) 2;

(c) R^ is hydrogen or a substituted or tinsubstituted
group selected from aryl, heteroaryl, or a Ci-e
aliphatic group,, and R^' is hydrogen; and

(d) R^ is selected from -R, -OR, or -N(R*)2/ wherein
R is selected from hydrogen, Ci-e aliphatic, 5-6
membered heterocyclyl , phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring P is substituted by up to three
substituents selected from -halo, -CN, -NO2/
-N(R^)2# optionally substituted Ci-e aliphatic
group, -OR, -C(0)R, -CO2R/ .-CONH(R^) , -N(R*)-COR,
-N(R^)C02R, -S02N(R*)2, -N(R*)S02R,
-N(R^)COCH2N(R^)2, -N(R^)C0CH2CH2N(R^)2, or
-N(R^)COCH2CH2CH2N(R*)2/ wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

Representative compounds of formula IVb are
shown below in Table 10.

-181-

Table 10.

IVb-10

IVb-11

IVb-12

-182-

IVb-13 ivb-14 IVb-15

Me

In another embodiment, this invention provides
a composition comprising a compoiand of formula IVb and a
phaanaaceutically acceptable carrier.

Another aspect of this invention relates to a
5 method of treating or preventing an Aurora -2 -mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IVb or a pharmaceutical composition
10 thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IVb or a composition comprising said
15 compound.

Another aspect of this invention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
20 therapeutically effective amount of a compound of formula
IVb or a pharmaceutical composition thereof.

-183-

One aspect of this invention relates to a '
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof ,
which method comprises administering to the patient a
5 therapeutically effective amount of a compoxind of formula
IVb or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients- Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in

10 halting or slowing the progression of Alzheimer's ^
disease. Another method relates to inhibiting the \3
phosphorylation of p-catenin, which is useful for
treating schizophrenia.

Another aspect of this invention relates to a

15 method of inhibiting GSK- 3 activity in a patient, which
method comprises administering to the patient a compbimd
of formula ivb or a composition comprising said compound.

Another method relates to inhibiting Aurora- 2
or GSK- 3 activity in a biological sample, which method

20 comprises contacting the biological sample with the
Aurora -2 or GSK-3 inhibitor of formula IVb, or a

pharmaceutical composition thereof, in an amount O
effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to •
25 the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula rvb, as described
above.

Another embodiment of this invention relates to
3 0 compounds of formula IVc :

-184-

r2

H
IVc

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:

is nitrogen or C-R® and is nitrogen or CH, wherein
one of Z^ or Z^ is nitrogen;
5 and are independently selected from T-R^ or L-Z-R^,

or R* and R^ are taken together with their intervening
atoms to foarm a fused, unsaturated pr partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,

10 wherein each substitutable ring carbon of said fused

ring formed by R* and R^ is independently substituted
by oxo, T-R^, or L-Z-R^, and each substitutable ring
nitrogen of said ring formed by R* and R^ is
independently substituted by R*;

15 R^ is T-{Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected

20 from nitrogen, oxygen or sulfur, wherein each

substitutable ring carbon of Ring D is independently
substituted by oxo, T-R^, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
substituted by -R^;

25 T is a valence bond or a C1.4 alkylidene chain;

-185-

Z is a Ci-4 aikylidene chain;

L is -0-, -S-, -SO-, -SO2-, -N(R*)S02-, -SOaNCR*)-/
-N(R*)-, -CO-, -CO2-, -N(R*)CO-, -N{R®)C(0)0-,
-N(R*)CX)N{R*)-, -N{R«)S02N(R*)-, -N(R*)N(R*)-,
5 -C{0)N{R*)- , -0C(0)N{R«) -C(R*)20-, -C(R*)2S-,

-.C(R*)2S6-, -C(R*)2S02-, -C(R*)2S02N(R*) -C (R*) 2N (R*) - ,
-C{R*)2N (R^)C{0)-, -C(R*)2N(R*)C(0)0-, -C (R*) =NN (R*) - ,
-C(R*)=N-0-, -C(R*)2N(R*)N(R*)-, -C (R*) 2N (R*) S02N(R*) - , or
-C (R*) 2N (R*) CON (R*) - ,-

10 R^ and R*' are independently selected from -R, -T-W-R®, or .

r2 and R*' are taken together with their -intervening ^
atoms to form a fused, 5-8 membered, unsatiirated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each

15 substitutsdjle ring carbon of said fused ring formed by

R^ and R^* is independently substituted by halo, 0x0, ,
-CH, -NO2, -R', or -V-R®, and each substitutable ring
nitrogen of said ring formed by R^ and R^' is
independently substituted by R*;

20 R^ is selected from -R, -halo, -OR, -C(=0)R, -CO2R,

-COCOR, -COCH2COR, -NO2, -CN, -S{0)R, -S(0)2R, -SR,

-N(R*)2/ -CON(r')2, -S02N(r'')2, -0C(=0)R, -n(r'')cor, Q

-NCR') C02(Ci-6 aliphatic) , -N(R*)N(R*) 2, -C=NN{R*)2/

-C=N-OR, -N (R') con (R') 2/ -N (R') SO2N (r') 2/ -N (R*) SO2R, or

25 -0C(=0)N{R'')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci-g
aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
30 atoms; *

each R* is independently selected from -R^, -COR',

-CO2 (optionally siibstituted Ci^g aliphatic) , -C0N{r'')2,
or -SO2R';

-186-

each is independently selected from -R, halo, -OR,

-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -C0N(R*)2, -S02N(R'')2, -OC(=0)R, -N{R*)COR,
-N(R*) C02( optionally s\ibstituted Ci-g aliphatic) ,
5 -N(R*)N(R*)2, -C=NN(R*) 2, -C=N-OR, -N (R*) CON (R*) 2,

-N(R'*)S02N(R^)2, -N(R*)S02R, or -0C(=0)N(R^)2;
Vis -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N.(R^)-,
-N(R*)-, -CO-, -CO2-, -N(R^)CO-, -N{R^)C(0)0-,
-N(R*) CON(R^)-, -N(R^)S02N(R^) -, -N (R^) N (R«) - ,

10 -C(0)N(R*)-, -0C(O)N(R*).-, -C(R^)20-, -G(R^)2S-,

-C(R®)2SO-, -C(R*)2S02-/ -C(R*)2S02N(R^)-, -C (R^) 2N(R^) - ,
-C (R^)2N.{R*)C(0) -, -C(R*)2N(R«)C(0)0- , -C (R^) =NN(R^) - , •
-C (R*) =N-0- , -C (R*) 2N (R*) N (R*) - , -C (R^) 2N (R^) SO2N (R*) - , or
-C (R*) 2N (R*) CON (R*) - ;

15 W is -C(R^)20-, -C(R*)2S-, rC(R*)2SO-, -C(R*)2S02-,
-C(R'')2S02N(R*)-, -C{R*)2N(R*)-, -CO-, -Cpa-,
-C(R*)OC{0)-, -C(R*)OC(0)N(R*)-, -C (R*) 2N (R*) CO- ,
-C(R*)2N(R*)C(0)0-, -C(R*)=NN(R«)-, -C(R*)=N-0-,
-C(R*)2N(R*)N(R«)-, -C(R«)2N(R*>S02N(R*)-,

20 -C(R*)2N(R*)C0N(R^)-, or -CON(R*)-;

each R* is independently selected from hydrogen or an
optionally sxibstituted C1.4 aliphatic group, or two R®
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered

25 heterocyclyl or heteroaryl ring;

each r"' is independently selected from hydrogen or an
optionally substituted C1.6 aliphatic group, or two r'
on the same nitrogen are teOcen together with the
nitrogen to form a 5-8 membered heterocyclyl or

30 heteroaryl ring; and

R« is .selected from -R, halo, -OR, -C(-0)R, -CO2R, -COCOR,
-NO2, -CN, -S(0)R, -SO2R, -SR, -N{R*)2, -CON(R*)2,
-S02N(R*)2/ -OC(=0)R, -N(R*)COR, -N (R*) CO2 (optionally

-187-

sxibstituted Ci-6 aliphatic) , -N (R^)N (R^) 2, -C=:NN(R^)2/
-C=N-OR, -N(R^)CON(R*)2, -N (R^) SO2N (R^) 2/ -N (R^) SO2R, or

-0C(=0)N(R*)2-

Preferred rings formed by R* and FX of formula
5 IVC' include a 5-, S-, or 7-meinbered unsaturated or
partially xinsaturated ring having 0-2 heteroatoms ^
wherein said K'^/bX ring is optionally substituted. This
provides a. bicyclic ring system containing a pyridine
ring. Preferred pyridine ring systems of formula ivc are
10 shown below.

Z2

V

IVC-A IVc-B IVC-C

HN-^ HN^ HN-^

IVc-D IVc-B IVc-P

HN

UN

IVC-J

IVc-K

IVC-L

-188-

IVC-W

More preferred pyridine ring systems of formula
IVc include IVc-A, IVc-B, IVc-D, IVc-B, IVc-J, IVc-P, and
JVc-V, most preferably rvc- A/ IVc-B, IVc-D, IVc-B, and
IVc- J. Even more preferred pyridine ring systems of
5 formula IVc are those described above, wherein is
nitrogen and 2^ is CH

Preferred groups of fozmula IVc include
hydrogen, alkyl- or di alky 1 amino, acetamido, or a C1.4
• aliphatic group such as methyl, ethyl, cyclopropyl, or

10 isbpropyl.

Preferred groups of formula IVc include T-R^
or L-Z-R^ wherein T is a valence bond or a methylene, L is

-S-, or -N(R*)-, -C(R^)20-, -CO- and R^ is -R,
-N(R^)2, or -OR, Examples of preferred R^ groups include

15 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,

morpholinyl / piperazinyl , methyl , ethyl , cyclopropyl ,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl , alkyl- or dialkylamino such as ethylamino

20 or dimethylamino, alkyl- or dialkylaminoalkoxy such as'

-189-

dimethylaminopropyloxy, acetatnido, optionally substituted
phenyl such as phenyl or halo- substituted phenyl.

.The ring formed when the R* and groups of
formula IVc are taken together may be siabstituted or
5 unsxabstituted. ■ Suitable substituents include -R, halo,
-0(CH2)2-4-N(R*)2. -0{CH2)a.4-R, -OR,. -N (R*) - (CH2) 2-4-N(R*) 2/
-N(R*)-(CH2)2.4-R» -C(=0)R, -CO2R, -COCOR, -NO2, -CN,
-S(0)R, -SO2R, -SR, -N(R*)2, -CON(R*)2, -S02N(R*)2,
-OC{=0)R, 7N(R'*)COR, -N (R*)C02 (optionally substituted Ci-s

10 aliphatic), -N(R*)N(R*)2, -C=NN(R*)2/ -C=N-OR,

-N(R^)CON(R*)2. -N(R*)S02N(R*)2/ -N(R*)S02R, or W
-OC{:=0)N(R^)2/ R and are as defined above. Preferred
R^/R^ ring svibstituents include -halo, -R, -OR, ^COR,
•CO2R, -C0N(R*)2r -CN, -0(CH2)2-4-N(R*)2/ -0(CH2)2-4-R# . # -NO2

15 -N(R*)2/ -NR^COR, -NR^SOzR, -S02N(R^)2 wherein R is hydrogen •
or an optionally sxibstituted Ci-e aliphatic group.

The R^ and R^' groups of formula IVc may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.

20 Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-merabered carbocyclo ring.
These are exemplified in the following formula rvc ^
compounds having a pyrazole -containing bicyclic ring
system:

-190-

Preferred substituents on the R^/R^' fused ring
of formula IVc include one or more of the following :
-halo, -N(R^)2, -Ci.4alkyl, -C1-4 haloalkyl, -NO2, -0(Ci.4 .
alkyl), -C02(Cx.4 alkyl) , -CN, -SO2 (C1-4 alkyl) , -SO2NH2,
5 -0C(0)NH2, -NH2S02(Ci.4 alkyl) , -NHC (O) {C1-4 alkyl) ,

-C(0)NH2/ and -CO (C1.4 alkyl) , wherein the (C1.4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (C1.4 alkyl) group is methyl-

When the pyrazole ring system of formula IVc is

10 monocyclic, preferred groups include hydrogen or a
substituted or unstabstituted group selected from aryl,
heteroaryl, or a Ci-e aliphatic group- Examples of such
preferred R^ groups include H, methyl, ethyl, propyl, ,
cyclopropyl , i -propyl , cyclopentyl , hydroxypropyl ,

15 methoxypropyl, and benzyloxypropyl - A preferred R^' group
is hydrogen.

When Rin^ D of formula IVc is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.

20 When Ring D of formula IVc is bicyclic,

preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl , quinolinyl,
indolyl , isoindolyl , indolinyl , benzo [b] f uryl ,
benzo [b] thiophenyl , indazolyl , benzothiazolyl ,

25 cinnolinyl, phthalazinyl, quinazolinyl , quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl •

On Ring D of formula IVc, preferred T-R^ or
V-z-R^ substituents include -halo, -CN, -N02f -N(R*)2r
optionally substituted Ci-e aliphatic group, -OR, -C(0)R,

30 -CO2R, -CONH(R^), -N{R^)COR, -N(R^)C02R. -S02N{R^)2,

-N(R*)S02R/ -N(R^)COCH2N(R^)2/ -N(R^) COCH2CH2N (R^) 2, and
-N(R^)C0C3l2CH2CH2N(R^)2, wherein R is selected from
hydrogen, Ci.g aliphatic, phenyl, a 5-6 membered

-191-

heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred substituents include -Cl, -Br, -F, -CN,
-CF3, -cook, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSOsMe,
-NHS02Et, -NHSO2 (n-propyl) , -NHSO2 (isopropyl) , -NHCOEt,
5 -NHCOC3I2NHCH3, -NHCOCH2N(C02t-Bu)CH3/ -NHCOCH2N (CH3) 2r
-NHCOC2l2CH2N(CH3)2/ -NHCOCH2CH2CH2N(CH3) 2/

-NHCO(cycl6propyl) , -NHCO(isobutyl) , -NHCOCH2(morpholin-4-
yl) , -NHCOCH2CH2 (morpholin-4-yl) , -NHCOCH2CH2CH2 (morpholxn-
4-yl), -NHCO2 (t -butyl ) , -NH(Ci.4 aliphatic) such as -NHMe,
10 -N(Ci.4 aliphatic) 2 such as -NMe2/ OH, -0(Ci.4 aliphatic)
such as -OMe, C1.4 aliphatic such as methyl, ethyl,
cyclopropyl> isopropyl, or t -butyl, and -C02(Ci-4
aliphatic) •

Preferred groups of formula IVc, when
15 present, include R, OR, and N{R*)2. Examples of preferred
R^ include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH,
N(CH3)2CH2CH20, (piper idin-l-yl)CH2CH20, and NH2GH2CH2O.

Preferred formula IVc compounds have one or
more, and more preferably all, of the features selected
20 from the group consisting of:

(a) R'^ is hydrogen, alkyl- or dialkylamino,

acetamidb, or a C1-4 aliphatic group and R^ is
T-R^ or Ii-Z-R^, wherein T is a valence bond or a
methylene and R^ is -R, -N(R*)2/ or -OR; or R"" and
25 R^ are taken together with their intervening

atoms to form a fused, unsaturated or partially
unsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein each substitutable ring carbon
30 of said fused ring formed by R"^ and R^ is

independently substituted by 0x0, T-R^, or L-Z-
R^, and each substitutable ring nitrogen of said

-192-

ring formed by R"" and is independently
siibstituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

(c) Ring D is a 5-7 membered monocyclic or an 8-10
membered bi cyclic aryl or heteroaryl ring; and

(d) R^ is ^R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are taken together to form an optionally
siabstituted benzo ring.

More preferred compounds of formula IVc have
one or more, and more preferably all, of the features
selected from the group consisting of:

(a) R^ is T-R^ or L-Z-R^ wherein T is a valence bond
or a methylene and R^ is selected from -R, -OR,
or -N(R^)2/ wherein R is selected from hydrogen,
Ci-6 aliphatic, or 5-6 membered he terocyclyl,
phenyl, or 5-6 membered heteroaryl; or R"^ and R^
are taken together with their intervening . atoms
to form a benzo, pyrido, cyclopentc, cyclohexo,
cyclohepto, thieiio, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by R=* and R*' is independently
siabstituted by oxo, T-R^, or L-Z-R^, and ea<3h
siabstitutable ring nitrogen of said ring formed
by R"" and R^ is independently siabstituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-
10 membered bicyclic aryl or heteroai^l ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci.e aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

-193-

(d) is selected from -R, -halo, -OR, or -N{R^)2#
wherein R is selected from hydrogen, Ci.g
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -NCR*)

Even more preferred compounds of formula IVc
have one or more, and more preferably all, of the
features selected from the group consisting of:
<a) R* is hydrogen methyl, ethyl , propyl ,

cyclopropyl, isopropyl, methylamino or ' acetamido
and R^ is selected from 2-pyridyl, 4-pyridyl,
pyrrol idinyl> piper idinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino ,
alkoxyalkyl, allcyl- or dialkylamino, alkyl- or
dialkylaminoalkoxy, acetamido, optionally
Slabs tituted phenyl, or methoxymethyl ; or R* and
R^ are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with -halo, -R, -OR, -COR, -CO2R,
-CON(R*)2/ -CN, -0(CH2)2-4-N(R*)2/ -O (CH2) 2-4-Rr -NO2
-N(R*)2f -NR^COR, -NR*S02R/ or -S02N(R*)2, wherein
R is hydrogen or an optionally sxobstituted Ci-g
aliphatic group;
(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl ring
optionally sxibstituted with one or two groups
selected from -halo, -CN, -NO2, -N(R*)2,
optionally substituted Ci-e aliphatic, -OR,
-C(0)R, -CO2R, -CONH(R*) , -N(R*)COR, -N(R^)C02R,
-S02N(R*)2, -N(R*)S02R, -N(R^) C0CH2N(R*) 2,
-N(R^)COCH2CH2N(R*)2/ or -N{R^) GOCH2CH2CH2N (R*) 2;

-194-

(c) is hydrogen or a substituted or unsubstituted
group selected from aoryi/ heteroaryl, or a Ci.s
aliphatic group, and R^' is hydrogen; and

(d) R^ is selected from -R, -OR, or -N{R^)2/ wherein
R is selected from hydrogen, Ci-e aliphatic, 5-6
membered heterocyclyl , phenyl, or 5-6 membered
heteroaryl> and L is -O^, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2,
-N(R*)2r optionally sxabstituted Ci-e aliphatic
group, -OR, -C{0)R, -CO2R, -CONH(R*), -N{R*)COR,
-N{R*)C02R, -S02N(R*)2# -N(R*)S02R,
-N(R^)COCH2N(R*)2/ -N(R^)COCH2CH2N(R*)2/ or

-N (R^)COCH2CH2CH2N(R*) 2 # wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring*
Representative compounds of formula IVc are

shown below in Table 11.
Table 11 .

IVc-1 IVc -2

-195-

IVc-4 IVc-5 . IVc-6

IVc-7 IVc-8 IVc-9

IVc-10 IVc-11 IVc-12

In another embodiment, this invention proyi^ies
a composition comprising a confound of formula IVc auid a
pharmaceutically acceptable carrier.

Another aspect of this invention relates to a
method of treating or preventing an Aurora- 2 -mediated
disease with an Aurora-2 inhibitor, which method
cott5)rises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IVc or a pharmaceutical composition
thereof •

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient.

-196-

which method comprises administering to the patient a
compound of formula IVc or a composition comprising said
compound.

Another aspect of this invention relates to a
5 method of treating or preventing a GSK- 3 -mediated disease
with a GSK- 3 inhibitor, which method conqprises
administering to a patient in need of such a treatment a
therapeutically effective amoiont of a compound of formula
IVc or a pharmaceutical composition thereof.

10 One aspect of this invention relates to a

method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amo\iht of a compound of formula

15 IVC or a pharmaceutical composition thereof- This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's

20 disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for
treating schizophrenia.

Another aspect of this invention relates to a-
method of inhibiting GSK-3 activity in a patient, which

25 method comprises administering to the patient a compound
of formula IVc or a composition comprising said compound.

Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the

30 Aurora-2 or GSK-3 inhibitor of foimula IVc, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to
the inhibition of Aurora- 2 or GSK-3, tor the treatment of
a disease alleviated thereby, . is pref erably carried out
with a preferred conrpound of formula IVc, as described
above.

Another embodiment of this invention relates to
compounds of formula IVd:

IVd

or a pharmaceutically acceptable derivative or prodrug

thereof, wherein:

is nitrogen br C-R* and 2=* is nitrogen or CH, wherein
one of or Z^ is nitrogen;

Q' is selected from -C(R^') 2-, 1, 2-cyclopropanediyl, 1,2-
cyclobutanediyl, or l , 3 - cyclobutanediyl ;

R* and R^ are independently selected from T-R' or L-Z-R',
or R* and ^ are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrog^,
wherein each substitutable ring carbon of said fused
ring formed by R* and R^ is independently substituted
by oxo, T-rS or L-Z-R^, and each sxibstitutable ring
nitrogen of said ring formed by r'' and R*" is
independently substituted by R*;

R^ is T- (Ring D) ;

-198-

Ring D is a 5-7 membered monocyclic ring or 8-10 metnbered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl/ said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
5 from nitrogen, oxygen or sulfur, wherein each

substitutable ring carbon of Ring D is independently
substituted by oxo, T-R®, or V-Z-R^, and each
substitutable ring nitrogen of Ring D is independently
Slabs tituted by -R*;

10 T is a valence bond or a Ci.4 alkylidene chain, wherein
r) when Q' is -C(R^')2- a methylene group of said C1-4

alkylidene chain is optionally replaced by -0-, -S-,
-N(R^)-, -CO-, -CONH-, -NHCO-, -SO2-/ -SO2NH- / -NHSO2-/
-CO2-, -0C{0)-, -OC(0)NH-, or -NHCO2-;

15 Z is a Ci-4 alkylidene chain;

L is -O-/ -S-, -SO-, -SO2-, -N(R^)S02-, -SOzNCR^)-,
-N(R^)-, -CO-, -CO2--, -N(R^)CO-, -N(R^)C(0)0-,
-N(R^)CON(R^) -, -N(R^)S02N(R^)-, -N (R^) N (R^) - ,
-C(0)N(R^)-, -0C(0)N(R^)-, -C(R^)20-, -C(R^)2S-,

20 -C(R^)2SO-, -C(R^)2S02-, -C{R^)2S02N(R^)-, -C(R^)2N(R^)-,

-C(R^)2N(R^)C(0)-, -C(R^)2N(R^)C{0)0-, -C (R^) =NN (R^) - ,
; . -C(R^)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or

-C(R^)2N(R^)CON(R^) -;
r2 and R^' are independently selected from -R, -T-W-R^, or

25 R^ and R^' are taken together with their intervening

atoms to form a fused, 5-8 membered, tinsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by

30 R^ and R^' is independently substituted by halo, 0x0,

-CN, -NO2, -R^r or -V-R^, and each substitutable ring
nitrogen of said ring formed by R^ and R^ is
independently substituted by R*;

-199-

r3 is selected from -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -S(0)2R, -SR,
-N(R'*)2, -C0N{R'')2, -S02N(R')2, -0C(=0)R, -.N(R')C0R,
-N(R"')C02(Ci-6 aliphatic) , -N (R*) N(R*) 2, -C=NN(R*)2,
-C=N-OR, -N(R'')C0N(R')2, -N(R'')S02N(R'')2/ -N(R*)S02R, or
-0C(=0)N(R')2;

each R is independently selected from hydrogen or an "
optionally svibstituted group selected from Ci.g
aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R* is independently selected from -R', -COR',

-CO2 (optionally s\jbstituted Ci-g aliphatic) , -CON(r')2/
or -SO2R';'

each is independently selected from -R, halo, -OR,

-C(=0)R, -CO2R/ -CX)COR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -CON(R*)2, -S02N(R*)2, -OC(=0)R, -N(R*)COR,
-N(R*)C02 (optionally siabstituted Ci-e aliphatic) ,
-N(R*)N (R*)2, -C=MN(R*)2, -C-N-OR, -N (R*) CON (R*) 2,
-N(R*)S02N(R*)2, -N{R'*)S02R, or -OC (=0)N(R*) 2;

V is -0-, -S-, -SO-, -SO2-, -N(R*)S03-, -S02N(R*)-,
-N(R^)-, -CO-, -CO2-, -N(R*)C0-, -N(R*)C(0)0-,
-N(R^)CON(R*)-, -N(R*)S02N(R*)-, -N(R*)N(R«) -,
-C(0)N(R^)-, -OC(0)N(R*)-, -C(R*)20-, -C(R*)2S->
-C(R«)2SO-, -C(R^)2S02-, -C(R«)2S02N(R*)-, -C(R«)2N(R*)-,
-C(R«)2N(R^)C(0)-, -C(R«)2N(R^)C(0)0-, -C (R*) =NN (R«) - ,
-C(R^)=N-0-, -C(R^)2N(R«)N(R^)-, -C (R^JaN (R*) S02N(R«) - , <
-C (R^-) 2N (R^) CON (R^) - ;

W is -C(R^)20-, -C(R«)2S-, -C(R*)2S0-, -C(R^)2S02-,
-C(R«)2S02N(R^)-, -C(R^)2N(R*)-, -CO-, -CO2-,
• -C{R^)OC(0) -C(R«)OC(0)N(R^) -C (R*) 2N (R^) CO- ,
-C(R^)2N(R^)C(0)0-, -C(R*)=NN(R^)-, -C(R^)=N-0-,

-C(R^)2N(R^)N{R^)-, -C(R^)2N(R^)S02N(R^)-,
-C{R^)2N(R^)C0N(R^)-, or -CON(R^)-;
each R^ is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R^
5 groups on the same nitrogen atom are taken • together

with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R^' is independently selected from hydrogen or a C1-4
aliphatic group, or two R®' on the same carbon atom are
10 taken together to form a 3-6 membered carbocyclic ring;

J each r"' is independently selected from hydrogen or an

optionally substituted Ci-e aliphatic group, or two r"'
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or .
15 heteroaaryl ring; and

R® is selected from -R, halo, -OR, -C(=0)R, -CO2R/ -COCOR,
-NO2, -CN, -S(0)R, -SO2R, -SR, -N(R^)2/ -CON(R*)2,
-S02N(R^)2/ -OC(=0)R, -N(R^)COR, ~N (R*) COaC optionally
substituted Ci-6 aliphatic) , -N(R*)N(R^)2, -C=NN(R*)2r
20 -C=N-OR, -N(R^)CON(R^)2, -N(R^)S02N(R^)2, -N(R*)S02R, or

-0C(=O)N(R^)2.

) Preferred rings formed by R^ and R^ of foarmula

IVd include a 5-, 6-, or 7 -membered tinsaturated or
partially unsaturated ring having 0-2 heteroatoms,
25 wherein said rVR^ ring is optionally substituted. This
provides a bicyclic ring system containing a pyridine
ring. Preferred pyridine ring systems of formula IVa are
shown below.

IVd-W

-201-

IVd-B

Oil,

rvcL-c

MN
IVd-E

IVd-P

HN^

IVd-K

IVd-L

rvd-R

IVd-V

-202-

More preferred pyridine ring systems of formula
IVd include IVd-A, IVd-B, IVd-D, iVd-E, IVd-J, IVd-P, and
rvd-V, most preferably IVd-A, iVd-B, iVd-D, IVd-E, and
IVd- J. Even more preferred pyridine ring systems of
5 formula IVd include those described above, wherein is
nitrogen and is CH.

Pref erred groups of formula IVd include
hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
10 isopropyl.

Preferred groups of formula IVd include T-R^
or L-Z-r' wherein T is a valence bond or a methylene, L is
-0-, -S-, or -N(R*)-, -C(R*)20-, -CO- and r' is -R,
-1>HR*)2, or -OR. Examples of preferred R^ groups include

15 2-pyridyl, 4-pyridyl, pyrrol idinyl , piperidinyl,

mbrpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t -butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxsralkyl such as methoxymethyl or
methoxyethyl, alkyl- or dialkylamino such as etliylamino

20 or dimethylamino, alkyl- or dialkylaminoalkoxy such as

dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo- substituted phenyl -

- The ring formed when the R* and R'^ groups of
formula IVd are tcJcen together may be substituted or

25 unsubstituted. Suitable substituents include -R, halo,
-0(CH2)2-4-N(R*)2/ -0(CH2)2-4-R, -OR, -N(R*)-(Cai2)2-4-N(R*)2/
-N(R*)- (CH2)2-4-R, -C(=0)R, -CO2R, -COCOR, -NO2, -OJ,
-S(0)R, -SO2R, -SR, -N(R*)2, -CON(R*)2/ -S02N(R'*)2/
-0C(=0)R, -N(R'*)COR, -N(R*)C02 (optionally substituted Ci-g

30 aliphatic), -N (R*)N (R*) 2, -C=NN(R*)2, -C=N-OR,
-N(R*)CON(R*)2, -N(R*)S02N(R*)2, -N(R*)S02R, or
-0C(=0)N(R*)2/ R and R* are as defined above. Preferred
R*/R^ ring substituents include -halo, -R, -OR, -COR,

10

-203-

-COsR, -CON{R^)2. -Ca^/ -0(CH2)2-4-N(R^)2/ -O (CH2) 2-4-R/ . -NO2
-N(R*)2, -NR^COR, -NR^SOaR, -S02N(R^)2 wherein R is hydrogen
or an optionally siobstituted Ci-e aliphatic group.

The R^ and R^' groups of formula IVd may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially iinsaturated 6-merobered carbocyclo ring.
These, are exemplified in the following formula IVd
compounds having a pyrazole -containing bicyclic ring
system:

NH

NH I NH

, and

NH

Preferred sxibstituents on the R^/R^' fused ring
of formula IVd include one or more of the following :
-halo, -N(R*)2/ -C1.-4 alkyl, -C1-4 baloalkyl, -NO2, -0(Ci-4

15 alkyl), -C02(Ci.4 alkyl) , -CN, -SO2 (C1.4 alkyl) , -SO2NH2,
-OC(0)NH2, -NH2S02(Ci.4 alkyl) , -NHC{0) (Cx-4 alkyl) ,
-C(0)NH2, and -CO (C1-4 alkyl) , wherein the (C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (C1.4 alkyl) group is methyl.

20 When the pyrazole ring system of formula IVd is

monocyclic, preferred R^ groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a Ci.e aliphatic group. Exan?)les of such
preferred R^ groups include H, methyl, ethyl, propyl, ,

25 cyclopropyl, i -propyl, cyclopentyl, hydroxypropyl ,

-204-

methoxypropyl, and benzyloxypropyl • A preferred R^' group
is hydrogen •

When Ring D of formula IVd is monocyclic/
preferred Ring D groups include phenyl, pyridyl,
5 pyridazinyl, pyrimidinyl^ ajid pyirazinyl.

When Ring D of formula IVd is bicyclic,
preferred bi cyclic Ring D groups include naphthyl^
tetrahydronaphthyl , indanyl , benzimidazolyl , quinolinyl ; .
indolyl/ isoindolyl^ indolinyl, benzo [b] f uryl ,

1 0 benzo [b] thiophenyl , indazoly 1 , benzothiazolyl ,

cinnolinyl, phthalazinyl, cpiinazolinyl , quinoxazolinyl ,
1> 8-naphthyridinyl and isoquinolinyl .

On Ring D of formula IVd, preferred T-R^ or
V-Z-R^ substituents include -halo, -CN, -NO2, -N(R*)2r

15 optionally substituted Ci-6 aliphatic group, -OR, -C(0)R,
-CO2R, -CONH(R*), -N(R*)COR, -N(R*)C02R, -S02N(R*)2,
-N(R^)S02R, -N(R^)COCH2N(R*)2, -N(R^) COCH2CH2N(R*)2. and
-N(R^)COCH2CH2CH2N{R*)2, wherein R is selected from
hydr:ogen, Ci-e aliphatic, phenyl, a 5-6 membered

20 heteroaryl ring, or a 5-6 membered heterocyclic ring-
More preferred R^ substituents include -Cl, -Br, -F, -CN,
-CF3, -GOOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me,
-NHS02Et, -NHSOzCn-propyl) , -NHSO2 (isopropyl) , -NHCOEt,
-NHCOCH2NHCH3, -NHCOCH2N(C02t-Bu)CH3, -NHCOCH2N(CH3) 2#

25 -NHCOCH2CH2N{CH3)2/ -NHCOCH2CH2CH2N (CH3) 2#

-NHCO (cyclopropyl) , -NHCO (isobutyl) , -NHCOCH2 (morpholin-4-
yl) , -NHCOCH2CH2 (morpholin-4 -yl ) , -NHCOCH2CH2CH2 (morpholin-
4-yl), -NHC02(t-butyl) , -NH {C1-4 aliphatic) such as -NHMe,
-N{Ci.4 aliphatic) 2 such as -NMe2/ OH, -0(Ci-4 aliphatic)

30 such as -OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t -butyl, and -C02(Ci.4
aliphatic) .

-205-

Preferred R® groups of fojmula IVd, when
present, include R, OR, and N(R*)2. ExaTi5>les of preferred
R® include methyl, ethyl, NH2/ NH2CH2CH2NH/ N(CH3)2CH2CH2NH,
N(CH3)2CH2CH20, {piperidin-l-yl) Cai2CH20, and NH2CH2CH20-

Preferred 'Q' groups of • formula IVd include
-C(R^')2- or 1, 2 -cyclopropanediyl,. wherein each R^' is
independently selected from hydrogen or methyl • A more
preferred Q' group is -CH2-.

Preferred formula IVd compo\inds have one or
more, and more preferably all, of the features selected
from the group consisting of :

(a) R"" is hydrogen, alkyl- or dialkylamino,
acetamido, or a C1.4 aliphatic group and R^ is
T-R^ or L-Z-R^, wherein T is a valence bohd or a
methylene and R^ is -R, -N(R*)2/ or -OR; or R* and
R^ are taken together with their intervening •
atoms to form a fused, unsaturated or partially
unsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein each substitutable ring carbon
of said fused ring formed by R^ and R^ is
independently svibstituted by 0x0, T-R^, or L-Z-
R^, and each substitutable ring nitrogen of said
ring formed by R"^ and R^ is independently
substituted by R^;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene unit and wherein said methylene unit
is optionally replaced by -0-, -NH-, or -S-;

(c) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and

(d) R^ is -R or -T-W-R^ and R^' is hydrogen, or R^ and
R^' are taken together to form an optionally
substituted benzo ring-

-206-

More preferred compounds of foannula IVd hiave
one or more, and more preferably all, of the features
selected from the group consisting of:

(a) is T-R^ or L-Z-R^ wherein T is a valence bond
5 • or a. methylene and R^ is selected from -R, -OR,

or -N(R*)2/ wherein R is selected from hydrogen,
Ci-6 aliphatic, or 5-6 membered heterocyclyl ,
phenyl, or 5-6 membered heteroaryl; or R* and R^
are taken together with their intervening atoms
10 to form a benzo, pyrido, cyclopento, cyclohexo,

cyclbhepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by and R^ is independently
substituted by oxo, T-R^, or L-Z-R^, and each
15 siabstitutable ring nitrogen of said ring foarmed

. by R* and R^ is independently sxabstituted by R*;

(b) R^ is T-(Ring D) , wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-
10 membered bicyclic aryl or heteroaryl ring;

20 (c) R^ is -R and R^' is hydrogen, wherein R is

selected from hydrogen, Ci-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;

(d) is selected from -R, -halo, -OR, or -N(R*)2#
25 wherein R is selected from hydrogen, Ci.g

aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R^)-; and

(e) Q' is -C(R^')2- or 1, 2-cyclopropanediyl, wherein
30 each R^' is independently selected from hydrogen

or methyl.

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Even more preferred compounds of formula IVd
have one or more, and more preferably all, of the'
features selected from the group consisting of:

(a) R"" is hydrogen methyl, ethyl, propyl,

• cyclopropyl, isopropyl, methylamino or acetamido
and is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyaikyl, . alkyl- or dialkylamino, alkyl- or
dialkylaminoalkoxy, acetamido, optionally
Slabs tituted phenyl, or raethoxymethyl ; or R"^ and
R^ are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with -halo, -R, -OR, -COR, -CO2R/
-CON(R*)2/ -CN, -0(CH2)2-4-N(R*)2, -O (CH2) 2-4-R# -NO2
-N(R*)2/ -NR^COR/ -NR^SOgR, or -S02N(R*)2, wherein
R is hydrogen or, an optionally substituted Ci-g
aliphatic group;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaaryl ring
optionally s\abstituted with one or two groups,
selected from -halo, -CN, -NO2, -N(R^)2/
optionally substituted Ci-6 aliphatic, -OR,
-C(0)R, -CO2R, -CONH{R^), -N(R^)COR, -N(R*)C02R,
-S02N(R^)2. -N(R^)S02R, -N (R^) COCH2N (R*) 2,
-N(R^)COCH2CH2N(R^)2/ or -N (R^) COCHzCHsCHzNCR^) 2;

(c) R^ is hydrogen or a substituted or unsubstituted
group selected from aryl, heteroaryl, or a Ci-e
aliphatic group, and R^' is hydrogen; and

(d) R^ is selected from -R, -OR, or -N(R^)2, wherein
R is selected from hydrogen, Ci.e aliphatic, 5-6

-208-

membered heterocydyl/ phenyl, or 5-6 membered
heteroaryl, and L is or -NH-;

(e) Ring D is sijbstituted by up to three
sixbstituents selected from -halo, -CN, -NO2,.
-N(R*)2/ optionally siabstituted Ci-e aliphatic
group, -OR, -C(0)R, -CO2R, -CONH{R^) , -N(R*)COR
-N(R^)C02R, -S02N{R^)2, -N(R*)S02R,
-N(R^)COCH2N(R*)2/ -N(R^)C0CH2CH2N(R^)2/ or
-N(R^)COCH2CH2CH2N{R^)2, wherein R is selected
from hydrogen, C1.6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(f) Q\ is -CH2-.

Representative compounds of formula IVdare

shown below in Table 12-
Table 12 , v

IVd-4 IVd-5 IVd-.6

-209-
Me Me

HN^N HN*^

IVd-7 XVd-S

In another embodiment, this invention provides
a composition comprising a compound of formula IVd and a
pharmaceutically acceptable carrier.

Jtoother aspect of this invention relates to a
5 method of treating or preventing an Aurora -2 -mediated @
disease with an Aurora- 2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IVd or a pharmaceutical composition
10 thereof.

Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IVd or a composition con5>rising said
15 compo\ind.

Another aspect of this imrention relates to a
method of treating or preventing a GSK- 3 -mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

20 therapeutically effective amount of a compoiind of formula
IVd or a pharmaceutical composition thereof.

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,

25 which method comprises administering to the patient a

therapeutically effective amount of a compound of formula
IVd or a pharmaceutical composition thereof. This method

-210-

is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein/ which is useful in
halting or slowing the progression of Alzheimer's
5 disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for
treating schizophrenia.

Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
10 method comprises administering to the patient a compound
O of formula IVd or a composition comprising said compound.

Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
15 Aurora -2 or GSK-3 inhibitor of formula IVd, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3-

Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
20 a disease alleviated thereby, is preferably carried out
with a preferred compoiond of formula IVd, as described
( j above .

The compounds of this invention may be prepared
in general by methods known to those skilled in the art
25 for analogous compounds, as illustrated by the general
Schemes I -VII, the general methods that follow, and by
the preparative examples below.

-211-

Schemel

1 2 3 11

Reagents: (a) EtOH, EtaN, room temperature; (b) R^-QH (Q =

S, NH or O) or R^-CH2-M/catalyst (M is Al or Mg or Sn,

catalyst = Pd» or Ni"). ^

. Scheme I above shows a general route for the
preparation of the present compoiinds . The dichlorinated
starting material 1 may be prepared using methods similar
5 to the those reported in J. Indian. Cbem. Soc, 61, 690-
693 (1984) or in J". Med. C2iem. , 37, 3828-3833 (1994).
The reaction of 1 with aminopyrazole (or aminoindazole) 2
in a manner as described in Bioorg. Med. Cbem. Iretrt, 10,
11, 1175-1180, (2.000) or in J". Het. C2iem, 21, 1161-1167,

10 (1984) provides the versatile monochloro intermediate 3.
Conditions for displacing the dhloro group of 3 by R^-Q
will depend on the natxire of the Q linker moiety and are \3
generally known in the field. See, for example, »7. wfed.
Chem, 38, 14, 2763-2773, (1995) (where Q is an N-Link) ,

15 or Chem. PJiarm. Bull., 40, 1, 227-229, (1992) (S-Link) ,
or jr. Het. Chem., 21, 1161-1167, (1984) (O-Link) or
Bioorg. Med. Chem. Lett, 8,. 20, 2891-2896, (1998) (C-
Link) .

-212-

Scheme II

OH ,9 HN'^N

''Vn "V^'l' + ^/^H JL^ "Vl"

4 5 2 II

Reagents: (a) POCI3, PraN, llCC; (b) EtOH, EtaN, room
temperature. .

O. Scheme II above shows an alternative route for

the preparation of the present compoiinds. The starting
material 4 . may be prepared in a manner similar to that
described for analogous compounds- See Chiem. Heterocycl.
5 Coa^d,, 35, 1, 818-820 (1999) (where Q is an N-Link) ,
Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (NrLink) ,
Pestic. Sci, 47, 2, 103-114 (1996) (O-Link) , J". Med.
Chem. , 23, 8, 913-918 (1980) (S-Link) , or Pbarmazle, 43,
7, 475-476 (1988) (C-Link) . The chlorination of 4
10 provides intermediate 5. See J. Med. Chem. , 43, 22,

4288-4312 (2000) (Q is an N-Link) , Pestic. Sci, 47, 2,.
103-114 (1996) (O-Link) , J. Med. Chem.. 41, 20, 3793-3803
(1998) (S-Link), or J. Med. Chem., 43, 22, 4288-4312
(2000) (C-Link) . Displacement of the 4-Cl group in
15 intermediate 5 with aminopyrazole (or aminoindazole ) 2 to
provide compoiands of this invention may be performed
according to known methods for analogous compovmds. See
J. Med. caiera, , 38, 14, 2763-2773 (1995) (where Q is an N-
Link), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (O-
20 Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000)

(S-Link), or J. Med. Chem., 41, 21, 4021-4035 (1998) (C-
Link) .

-213-

Schetne III

9 II

Reagents: (a) POCI3; (b) EtOH, EtaN, room temperature; (c)
Oxone; (d) R^-QH (Q = S, NH or O) or R^-CHa-M/ catalyst {M
is Al or Mg or Sn, catalyst = Pd° or Ni**)

Scheme III above shows another alternative
route for preparing the present compounds . The starting
material 6 may be chlorinated to provide intermediate 7.
Displacement of the 4-chloro group in 7 with
aminopyrazole (or aminoindazole) 2 gives intermediate 8
which, upon oxidation of the methylsulf anyl group,
provides the methylsulf one 9. The methylsulf onyl group
of 9 may be displaced readily with R*-QH to give the
desired product 1. See j. Am. Chem. Soc. , 81, 5997-6006
(1959) (vdiere Q is auci N-Link)or in Bloorg. Med. caiem.
Iiett., 10, 8, 821-826 (2000) (S- Link).

-214-

Scheme IV

13 14 II

Reagents: (a) POCI3; (b) EtOH, EtaN, room temperature; (c)
R^-H (R = S, NH or O) ; (d) oxone; (e) R^-QH (Q = S, NH or
O) or R^-CH2-M/catalyst (M is Al or Mg or Sn, catalyst =
Pd** or Ni*')

Scheme IV above shows a general route for the
preparation of the present con5>ounds wherein R^ is a group
attached to the pyrimidine core via a nitrogen, oxygen or
5 sulfur heteroatom. The starting 4, 6-dihydroxy-2-
methylsulfanylpyrimidine 10 may be prepared as described
in J. Med. Cbem. , 27, 12, 1621-1629 (1984). The chloro
groups of inteirmediate 11 may be displaced sequentially
with aminopyrazole (or aminoindazole) 2 and then with

10 another amine (or alcohol or thiol) following procedures
similar to those reported in US Patent 2585906 (ICI,
1949) . The methylsulf anyl group of 13 may then be
oxidized to provide the methylsulf one 14, Displacement
of the methyl sulfonyl group of 14 gives the desired

15 product II.

-215-

SchemeV

Scheme V a±>ove shows general routes for the
preparation of compoxmds of formulae IVa, IVb, IVc^ and
IVd. Steps (a) and (b) are analogous to the
corresponding steps described in Scheme I above. See
Jndian *J. C2aein. Sect. B, 34, 9, 1995, 778-790; Chem.
Soc, 1947, 899-905; *J. Chem. Soc, 34, 9, 1948, 777^782
cuid Indian J". Chem., 1967, 467-470.

The synthetic 'transformations shown in Schemes
I -IV above are further illustrated by the following
methods.

Scheme VI

19 20 21

-216-

Scheme VI above shows a general route for
preparing the aryl guanidine intermediate used to prepare
compounds where Q is -C(R^')2-. The mono- or bis-
alkylation of 19 at step (a) to prepare compound 20 can
be achieved by using methods substantially similar to
those described by Jeffery, J. E., et al, J. Chem See,
Perkin Trans 1^ 1996 (21) 2S83-2589; Gnecco, D. , et al.
Org Prep Proced Int, 1996, 28 (4), 478-480; Fedorynski,
M. and Jonczyk, A., Org Prep Proced Int, 1995, 27 (3),
355-359; Suzuki, S, et al. Can J caiem, 1994, 71 (2) 357-
361; and Prasad, G. , et al, J Org Chem, 1991, (25), 7188-
7190. The method of step (b) to prepare compound 21 from
compound 20 can be achieved by using methods
substantially similar to those described by Moss, R. , et
al. Tetrahedron Lett, 1995, (48) , 8761-8764 and
Garigipati, R. , Tetrahedron Lett, ±990, (14) , 1969-1972.

The aryl guanidine intermediates prepared
according to Scheme VI may then be used to prepare the
compounds of this .invention by the methods described in
the above Schemes I-V and by methods Icnown to one skilled
in the art.

Scheme VII

o _ b u

22 23 24 .

25 26

Scheme VII above shows a general method that
may be used to prepare compoimds of formula II wherein Q

-217-

is 1,2-cyclopropanediyl. Cowpoiind 26 may then be used to
prepare the desired amino-pyrazole corapotinds using the
methods described above at Scheme I step (b) •
Method A > To a solution of 2,4-
5 dichloroquinazoline (12.69g, 63mmol) and 3-amino-5-
methylpyrazole (6.18g, 63mmol) in ethanol (220mL) is
added triethylamine (8.13mL, 63mmol) and the reaction
mixture is stirred for 3 hours at room temperature. The
pale yellow precipitate is then collected by filtration,
10 washed with cold ethanol and dried xander vacuum to give

(2-chlor6quinazolin-4-yl) - (5-methyl-2H-pyrazol-3-yl) - ©
amine.

The above -prepared (2-chloroquinazolin-4-yl) -
(5-methyl-2H-pyra2C)l-3-yl) -amine (155 rag, 0.6 mmol) and

15 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed in
tert-butanol (3 mL) over 20 h. The mixture is
concentrated In vacuo and the residue is suspended in
EtOH/H20 (lmL/3mL) . K2CO3 (83 mg, 0.6 mmol) is added and
the suspension is stirred for 2h at room temperature.

20 The solid that forms is collected and dried under vacutmi .
to give the product [2- (3-chlorophenylaraino) -quinazolin-
4-yll - (5-methyl-2H-pyrazol-3-yl) -amxne. 1;^

Method B , Sodium hydride (45 mg, 1.12 mmol) in
THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6

25 mmol) and the reaction mixture is stirred until

effervescence ceases. The THF is removed in vacuo and
the above -prepared (2-chloroquinazolin-4-yl) -(5-methyl-
2H-pyrazol-3-yl) -amine (150 mg, 0.51 mmol)) is added.
The reaction mixture is stirred at 100«>C for 20 h, then

30 poured into aqueous K2CO3 and stirred for 2h at room

temperature. The solid that forms is collected and re-
crystallized from ethanol to give the product [2- (3-

-218-

methoxyphenpxy) -quinazolin-4-yl] - ( 5 -methyl- 2H-pyrazol-3 -
yl ) -amine.

Method C . To a solution of 4-hycLroxy-2-
phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus
5 oxychloride (lOmL) is added- tripropyl amine (3 .02 mL, 15.8
mmol) and the reaction mixture is heated for 30 minutes
at 110 ®C. The excess phosphorus oxychloride is
evaporated in vacuo, the residue is poured on ice cold
aqueous NaHCOa and extracted with ethyl acetate. The

10 organic layer is washed with brine, dried, filtered and
C3 evaporated. The resulting residue is purified on flash

chromatography (SiOs/ hexane /AcOEt gradient) to give 4-
chloro- 2 -phenoxymethylcjuinazoline .

To a solution of the above 4-chloro-2-

15 phenoxymethylquinazoline (0.5 g, 1.85 mmol) in THF (30

mL) is added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69
mmol) and the reaction mixture is heated at 65 «C for 24
hours. Solvent is evaporated and ethanol is added. A
white solid forms and is collected by filtration and

20 dried iinder vacuum to give (5-cCyclopropyl-2H-J>yrazpl-3-
yl ) - (2 -phenoxymethyl-quinazolin-4 -yl) -amine .
/ Method D . To a solution of the above -prepared

( 2 - chloroquinazol in- 4 -y 1 ) - ( 5 - cyclopropyl - 2H-pyrazol - 3 -
yl) -amine (123 mg> 0.43 mmol) in THF (5 mL) is added

25 NiCla (dppp) (12 mg, 2 • 1.10'^ mol) , followed by IM

benzylmagnesium chloride in THF (2.15 mli, 2.15. mmol) .
The solution is heated at 50°C for 20 hours and the
reaction mixture is then quenched with aqueous NH4CI and
the product extracted in ethyl acetate. The solvent is

30 evaporated and the residue purified by flash

chromatography to yield the desired (2-benzyl-quinazolin-
4 -yl ) - ( 5 - cyclopropyl - 2H-pyrazol - 3 -yl ) - amin^ .

-219-

Method E . A solution of (2-chloroquinazolin-4-
yl) - (5-methyl-2H-pyrazol-3-yl) -amine (200 mg, 0 .77 tranol)
and 4-acetamidot:hiophenol (644 mg, 3,85 ramol) is refluxed
in tert-butanol (3 mL) over a 20 hour period.
Diethyiether- (10 mL) is added to the mixture and a solid
forms that is collected by filtration. This solid is
suspended in EtOH/H20 lmL/3mL) , then K2CO3 (110 mg, 0.8
mmol) is added and the suspension is stirred for 2h at
room temperature. A solid forms and is collected and
dried under vacuum to give the product [2-(4-
acetamidophenylsulf anyl) -quinazolin-4-yl] - (5-methyl-2H-
pyrazol - 3 -yl ) -amine .

Method F . To a solution of 2 , 4-dichloro- ;
5 , 6, 7, 8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-
amino-5-cyclopropylpyrazole (303 mg, 2,46 ramol) in DMF
(lOmL) is added triethylamine (0.357 mL, 2.56 mmol)
followed by sodium iodide (368 mg, 2.46 mmol) and the
reaction mixture is heated at 90 ""C for 20 h. The
reaction mixture is partitioned between ethyl acetate and
aqueous saturated NaHCOs. The organic layer is washed
with brine and evaporated in vacuo. The residue is
purified by flash chromatography (Si02> hexane/AcOEt
gradient) to give (2 -chloro-5 , 6,7, 8 - tetrahydroquinazolin-
4-yl) - (5-cyclopropyl-2H-pyrazol-3-yl) -amine.

The above -prepared (2-chloro-5, 6 , 7, 8-
tetrahydroquinazolin-4-yl) - (5-cyclopropyl-2ir-pyrazol-3-
yl) -amine is reacted with 2 -naphthalene mercaptan as
described in Method L to yield the desired (5-
cyclopropyl-2H-pyrazol-3-yl) - [2- (naphthalan- 2-
ylsulfanyl) -5,6,7, 8-tetrahydroquinazolin-4-yl] -amine.

Method G . A solution of (5-cyclopropyl-2H-
pyrazol-3-yl) - [2r (S-methoxycarbonylphenylsulf anyl) -
quinazolin-4-yl] ^amine (110 mg, 0.26 mmol) in a mixture

-220-

of THF/water (1/1/ 10 mL) is treated with IM LiOH (0.75
mL, 0.75 ramol) . The mixture is stirred for 20 hours at ■
room temperature and then neutralized with IM HCl (0.75
mL, 0,75 mmol) . A solid forms and is collected by
5 filtration to afford the desired [2- (3-

carboxyphenylsulf anyl) -quinazolin-4-yl] - (5-cyclopropyl-
2iI-pyrazol - 3 -yl ) - amine .

Method H > A solution of [2- (4- .
acetamidophenylsulfanyl) -7-methoxy-quinazolin-4-yl] - (5-
10 methyl-2H-pyrazol-3-yl) -amine (23 mg, 5.54.10"^ mol) in

0 dichloroe thane (3 mL) is treated with IM BBra in
dichloromethane (222 jiL, 2^21.10"^ mol). The mixture os
heated at 80 ^'C for 4 hours before IM BBra in DCM (222 \LL,
2 •21.10'* mol) is added. The reaction mixture is heated

15 at 80 for a further 3 hours . The solvent is evaporated
and methanol is added to the residue to quench residual
BBrs. The solvent is. evaporated In vacuo and this
operation repeated 3 times. IM HCl (2 mL) is added to the
solid residue and the suspension stirred at room

20 temperature for 15 hours. The solid is collected by

filtration auid suspended in a mixture water/EtOH (3/1, 8

1 J mL) . The mixture is neutralized with NaHCOa and stirred

for 2 hours at room temperatiire . The solid is then
collected by filtration, rinsed with water and diethyl
25 ether to give the desired [2- (4-acietamidophenylsulf anyl) -
7-hydroxy-quinazolin-4-yll - (5-methyl-2H-pyrazol-3-yl) -
amine.

Method I . To a solution of [2-(4-
acetamidophenylsulfanyl) -7-hydroxy-quinazolin-4-yl] - (5-
30 methyl -2ir-pyra2ol- 3 -yl) -amine (32 mg, 7.87.10^^ mol) in

DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10"*
mol) and the reaction mixture is heated to 80 **C. N-(3-

-221-

chloropropyDtnorpholine (39 mg, 2.36-10"* mol) is then
added, and the mixture is stirred at 80 '*C for 4 hours,
cooled to room temperature and the solvent is evaporated.
The resulting residue is purified by' flash chromatography
to afford the desired [2- (4-acetamidophenylsulfanyl) -7-
(3-moi:pholin-4-yl^propoxy) -quinazolin-4-yl] - (5-methyl-2H-
pyrazol - 3 -y 1 ) - amine .

Method J . To a solution of [2- (4-acetamido-
phenylsulfanyl) -7-nitroquinazolin-4-yl] - (5-methyi-2H-
pyrazol-3-yl) -amine (147 mg, 3.38.10"* mol) in methanol (5
mL) is added Pd/C 10% (40 mg) and the reaction mixture is
treated with hydrogen at balloon pressure at 45 °C for 20
hoTirs. The catalyst is filtered through a pad of celite
which is then washed with dilute HCl. The combined
yellow filtrate is evaporated and the resulting solid
residue is crystallized from methanol to afford the
desired [2- (4-acetamido-phenylsulf anyl) -7-
hydroxyaminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -

amine..

Method K . 1 2 - (4 -Acetamido-phenylsulf anyl ) - 7 -
nitroquinazolin-4-yl] - (5-methyl-2fr-pyrazol-3-yl) -amine
(182 mg, 4.18.10"* mol) is dissolved in a mixture
EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is
heated at 90 "C. Iron powder (93 mg) is added and the
mixtiire is stirred at 90 for 4 hours, cooled to room
temperature and filtered through a pad of celite. The
pad is washed with methanol and the combined filtrate is
concentrated in vacuo. The residue is purified by flash
chromatography (siOa, DCM/MeOH gradient) to give the
desired [2- (4-acetamido-phenylsulf anyl) -7-
aminoquinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine.

-222-

Method L. To a solution of 2,4-dichloro-S-
phenyl-pyrimidine (300 mg, 1.33 mmol). and 3 -amino- 5-
methylpyra25ole (129 mg, 1.33 ramol) in DMF (7 mL) is added
triethylamine (195 fiL, 1.40 ramol) followed by sodium
iodide (200 mg, 1.33 mmol) and the reaction mixture is
stirred for 15 hours at 90 "C. The resulting solution is
partitioned between ethyl acetate and water and the
organic phase washed with brine, dried over MgS04 then
concentrated in vacuo. The residue is triturated in
methanol and the resulting white solid collected by
filtration to afford {2-chloro-6-phenyl-pyrimidin-4-yl) -
(5-methyl-2H-pyrazol-3-yl) -amine (236 mg, 62%).

The above prepared (2-chloro-6-phenyl-
pyrimidin-4-yl) - (5-methyl-2H-pyra2ol-3-yl) -amine (60 mg,
0.21 mmol) is combined with 4-acetamidothiophenol (176
mg, l.OS ramol) in tert-butanol (5. ml.) and the mixture
heated at refliox for 20 hours. The reaction mixture is
cooled to room temperature and partitioned between ethyl
acetate and aqueous NaHCOg. The organic layer is washed
with brine, dried over MgS04 and concentrated in vacuo.
The resulting residue is purified by flash chromatography
(Si02, DCM/MeOH gradient) to afford [2- (4-acetamido-
phenylsulfanyl) -6 -phenyl -pyrimidin-4-yl] - (5-methyl-2H-
pyrazol-3-yl) -amine (74 mg, 85%)

Method M . To a suspension Of 4,6-
dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture
of EtOH/water (1/1, 140 mL) is added NaOH (2.33 g, 58.3
mmol) followed by 4 -methoaqrbenzyl chloride (7.90 mL, 58.3
ramol). The solution is stirred for 1.5 hours at 60
and then at room temperature for a fxirther 6 hours. The
resulting white precipitate is collected by filtration to
give 4, 6-dihydroxy-2- (4-methoxy-benzylsulfanyl) -
pyrimidine .

-223-

The above -prepared 4,6- dihydroxy- 2 - ( 4 -methoxy-
- benzylsulfanyl) -pyrimidine (2.5 9.46 mmol) is
suspended in POCI3 (20 mL) , and. tripropylamine (3.60 mL,
18.9 mmol) is added dropwise to the mixture. T he
5 • reaction is then heated at 110 «C for 4 hours. The brown
solution is cooled to room ten5>erature and the solvent is
evaporated. The residue is poured on ice cold NaHCOa and
the product is then extracted with ethyl acetate. The
organic phase is dried over MgS04/ concentrated in vacuo

10 and the residue is purified by flash chromatography (SiOa,
hexane/AcOEt gradient) to give 4, 6-dichloro-2- (4-methoxy-
benzylsulf anyl ) -pyrimidine .

To a solution of above -prepared 4 , 6-dichloro-2-
(4-methoxy-benzylsulf anyl) -pyrimidine (915 rag, 3.04 mmol)

15 and 3-amino-5-methylpyrazole (310 mg/ 3.19 mmol) in BuOH
(20 mL) is added diisopropylethylamine (0.56 mL, 3.19
mmol) followed by sodium iodide (455 mg, 3.04 mmol). The
reaction mixture is stirred for 15 hours at 120 **C. The
solvent is removed In vacuo and the residue is purified

20 by flash chromatography (SiOs, hexane/AcOEt gardient) to
give [6-chloro-2- (4-methoxy-benzylsulf anyl) -pyrimidin-4-
yl) - (5-methyl-2H-pyrazol-3-yl) -amine.

The above -prepared [6 -chloro-2- (4-methoxy-
benzylsulf anyl) -pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-

25 yl) -amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10
mL) is heated at 130 for 15 hours. The solvent is
then removed in vacuo and the residue is purified by
flash chromatography (SiOa, dichloromethane/MeOH gradient)
to give the desired product [2- (4-methoxy-

30 benzylsulfanyl) - 6- (4-methylpiperazin-l-yl) -pyrimidin-4-
yl ] - { 5 -methyl - 2H-pyrazol - 3 -yl ) - amine .

Method N . A solution of [2- (4-acetamido-
phenyl-sulf anyl) -6- (4-methoxyphenyl) -pyrimidin-4-yll - (5-

•224-

methyl-2H-pyrazol-3-yl) -amine (100 mg, 2-24,10"^ tnol) in
dichloroethane (5 mL) is treated with IM BBra in DCM (896
(IL, 8- 96. 10"* mol). The mixture is then heated at 80 «C
for 4 hours before IM BBra in DCM (896 |XL, 8 .96. 10"* mol)
5 is added. The reaction mixture is then heated at 80
for a further 3 hours. The solvent is evaporated and
methanol is added to the residue to quench any residual
BBra. The solvent is evaporated ±n vacuo and this
evaporation step is repeated 3 times. IM HC1(8 mL) is
10 added to the solid residue and the suspension is stirred
v^-^ at room temperature for 15 hours. The' solid is collected

by filtration and suspended in a mixture of water/EtOH
(3/1, 24 mli) . The mixture is neutralized with NaHCOs and
stirred for 2 hours at room temperature. The solid is
15 then collected by filtration, rinsed with water and with
diethyl ether to give [2- (4-acetamido-phenyl-sulf anyl) -6-
{4-hydroxyphenyl) -pyrimidih-4-yl] - ( 5 -methyl -2H-pyrazol-3-
yl ) -amine .

To a solution of the above -prepared [2-(4-
20 ' acetamido-phenyl-sulf anyl) -6- (4-hydroxyphenyl) -pyrimidin-
4-yl] - (5-methyl-2ir-pyrazol-3-yl) -amine (70 mg, 1.62.10"*
i J mol) in DMF (3 mL) is added potassium carbonate (134 mg,

9.71.10"* mol). The reaction mixture is. heated to 80«C
before l-dimethylamino-3-chloropropane hydrochloride (77
25 mg, 4.86.10"* mol) is added. The mixture is stirred at
80*»C for 4 hours, cooled to room temperature and the
solvent is evaporated. The residue is purified by flash
chromatography to afford the desired product {2-(4-
acetamido-phenyl-sulf anyl) -6- [4- (3-dimethylamino-
30 propoxy) -phenyl] -pyrimidin-4-yl} - (5-methyl-2H-pyrazol-3-
yl) -amine. .

Method O . To a solution of [6-methpxycarbonyl-
2- (4-propionylamino-phenyl-sulf anyl) -pyrimidin-4-yl] - (5-

-225-

methyl-2H-pyrazol-3-yl) -amine (2g, 4.85 mmol) in THP (100
mil) is added lithium borohydride (0.32 g, 14.5 ramol) .
The reaction mixture is stirred at 50*»C for 1.5 hours.
The reaction is then quenched with dilute HCl and
5 extracted with ethyl acetate. The organic layer is
successively washed with aqueous saturated NaHCOa and
brine, dried over MgS04 and evaporated. The solid residue
is triturated in ethyl acetate and the resulting white .
solid is collected by filtration to give the desired
10 product [6-hydroxymethyl-2- (4-propionylamino-phenyl-

sulf anyl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl> - ©
amine.

Method P . To a solution of 4/6-dichloro-2-
methylsulf anyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-

15 methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is

added diisopropylethylamine (4.69 mL, 26.9 ramol) followed
by sodiiam iodide (3.84 g, 25.6 mmol)- The reaction
mixture is stirred for 15 hours at 120 The solvent

is then removed in vacuo and the residue is purified by

20 flash chromatography (SiOa, hexane/AcOEt gradient) to give
[6-chloro-2-methylsulf anyl-pyrimidin-4-yl) - (5-methyl-2H-

pyrazol-3-yl) -amine. t3

The above -prepared [6-chloro-2-methylsulf ajiyl-
pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) -amine (2 .42 g,

25 9.46 mmol) is heated in morpholine (10 mL). at 130 for
15 hours . The solvent is then removed in vacuo and the
solid residue is triturated in EtOH and collected by
filtration to give [2-methylsulf anyl-6- (morpholin-4-yl) -
pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine.

30 To a suspension of the above -prepared [2-

methylsulf anyl-6- (morpholin-4-yl) -pyrimidin-4-yl] - (5-
methyl-2H-pyrazol-3-yl) -amine (500 mg, 1.63 mmol) in MeOH
(10 mL) is added a solution of oxone (3.0 g) in water (10

-226-

mil) . The reaction mixture is stirred at room temperature
for 15 hours and most of the solvent is evaporated* The
residue is partitioned between DCM and aqueous saturated
NaHCOa* The organic layer is washed with brine, dried,
5 filtered and evaporat-ed. The residue is triturated in
MeOH. and the resulting white solid is collected by
filtration to give [2-methylsulf onyl-6- (mo2:pholin-4-yl) -
pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine.

The above -prepared [2-methylsulf onyl-6-
10 (morpholin-4-yl) -pyrimidin-4-yl] - ( 5 -methyl -2H-pyra2ol-3-
3 yl) -amine (178 mg, .0.52 ramol) and 4-acetamidothidphenol

(176 mg/l.05 mmol) are reflxaxed in tert-butanol (5 mL)
over 20- h. The reaction mixture is cooled to room
temperature and partitioned between ethyl acetate and
15 aqueous NaHCOa. The organic layer is washed with brine,
dried over MgS04 and concentrated in vacuo. The residue
is purified by flash chromatography to give the desired
product [2- (4-acetamidophenylsulf anyl) -6- (morpholin-4-
yl) -pyrimidin-4-yl] - (5-methyl-2H-pyra2ol-3-yl) -amine.
20 In order that the invention described herein

may be more fully understood, the following examples are
set forth. It should be understood that these examples
are for illustrative purposes only and are not to be
construed as limiting this invention in any manner.

25

SYimiETIC EXAMPLES
The following HPLC methods were used in the
analysis of the compounds as specified in the Synthetic
Examples set forth below. As used herein, the term "Rt"
30 refers to the retention time observed for the compound
using the HPLC method specified.

-227-

HPLC-Method A:

Column: C18, 3 xim, 2.1 X 50 iran, "Lighting" by Jones
Chromatography.

Gradient: 100% water (containing 1% acetonitrile,
5 0.1% TFA) .to 100% acetonitrile (containing 0.1% TFA)

over 4.0 min, hold at 100% acetonitrile for 1.4 min
and return to initial conditions. Total run time 7.0
min. Flow rate: 0.8 mL/min.

10 HPLC-Method Bs

Column: C18, 5 vaa, 4.6 X 150 mm "Dynamax" by Rainin
Gradient: 100% water (containing 1% acetonitrile,,
0.1% TFA) to 100% acetonitrile (containing 0.1% TFA)
over 20 min, hold at 100% acetonitrile for 7.0 min

15 and return to initial conditions. Total run time

31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method C:

Colxamn: Cyano, 5 um, 4.6 X 150 mm "Micrpsorb" by

20 Varian.

Gradient: 99% water (0.1% TFA) > 1% acetonitrile
(containing 0.1% TFA) to 50% water (0.1% TFA), 50% £^
acetonitrile (containing 0.1% TFA) over. 20 min, hold,
for 8.0 min and return to initial conditions. Total

25 run time 30 min. Flow rate: 1.0 mli/min.

HPLC-Method D:.

Column: Waters (YMC) ODS-AQ 2.0x50mm, S5, 120A.
Gradient: 90% water (0.2% Formic acid), 10%
30 acetonitrile (containing 0.1% Formic acid) to 10%

water (0.1% formic acid), 90% acetonitrile.
(containing 0.1% formic acid) over 5.0 min, hold for

-228-

0.8 min and return to initial conditions. Total 3nan

time 7.0 min.

Flow rate: 1.0 mL/min.

5 HPLC-Method E;

Colvmua: 50x2. 0mm Hypersil CIS BDS;5 \m
Gradient: elution 100% water (0.1% TFA) , to 5% water
(0.1% TFA), 95% acetonitrile (containing 0.1% TFA)
over 2.1 min, returning to initial conditions after
10 2-3 min.

Flow rate: 1 mL/min.

Example 1 (5-Metliyl-2H-pyrazol-3-yl) - (2-plienylsulf anyl-
<3uinazolin-4-yl) -amine (IIa-1) : Prepared in a manner

15 similar to the aOaove described Method E to afford a pale
yellow solid, mp >3000C (dec.); NMR (DMSO) 5 2.07 (3H,
s)> 5.54 (IH, s), 7.38 (IH, m) , 7 .56-7.45 (4H, m) , 7.65 (2H,
m) , 7.73 (IH, m); 8.55 (IH, d) , 10.43 (IH, s) , 12.05(1H, br
S) ; IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525,

20 1476; MS 334.0 (M+H)*

Example 2 [2- (4-Clxlorophenylsulfanyl) -quinazolin-4-yll -
(5-methyl-2H-pyrazol-3-yl> -amine (IIa-2) : Prepared in a

msttiner similar to the above described Method E to afford
25 a pale yellow solid, mp 259-260«C; *H NMR (DMSO) § 2.12
(3H, s), 5.40 (IH, S), 7.60 (IH, t) , .7.64 (2H, d) , 7.76
(3H, d), 7.92 (IH, t), 8.70 (IH, d) 11.50 (IH, br s) ; IR
(solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339,

1286, 1219; MS 368.0 (M+H)*

30

Example 3 [2- (2,4-Dichlorophenylsulfanyl) -quinazolin-4-
yl] - (5-methyl-2H-pyrazpl-3-yl) -amine (Ila-3) : Prepared in

-229-

a maxiner similar to the above described Method E to
afford a pale yellow solid, rap 258-259''C; NMR (l»4SO) 8

2.12 (3H, S) , 5.40 (IH, s) , 7.54 (IH, t) , 7.63 (IH, m) ,

7.68 (IH, d) , 7.86 (IH, t) , 7.92 (IH, d) , 7.96 (IH, d) ,

5 8.66 (IH, d) 11.20 (IH, br s) ; IR (solid) 1623, 1610,

1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 (M+H) *

Example 4 [2 - (4 -Me thoxyphenylsul f anyl ) -qainazolin-4 -yl3 -
(5-methyl-2fl'-pyrazol-3-yl) -amine (IIa-4) : Prepared in a

10 manner similar to the above described Method E to afford
a pale yellow solid, mp 264-268''C; ^H NMR (DMSO) 6 2.04
(3H, s), 3.85 (3H, s) , 5.43 (IH, s) , 7.12 (2H, d), 7.53
(IH, t), 7.61 (3H, d), 7.84 (3H, t) , 8.63 (IH, d) , 11.09
(IH, br s), 12.30 (IH, br s) ; IR (solid) 1622, 1598,

15 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171, 1161; MS
364.1 (M+H)*

Example 5 [2- (2-Etliylphenylsulf anyl) -quiiiazolin-4-yl] - (5-
inethyl-2H-pyrazol-3-yl) -amine (IIa-5) : Prepared in a

20 manner similar to the above described Method B to afford
a pale yellow solid, mp 205-208*»C; ^H NMR (DMSO) 5 2.05
(3H, S), 5.19 (IH, S), 7.38 (IH, t) , 7.52-7.64 (3H, m) ,
7.68 (2H, d), 7.90 (IH, t) , 8.68 (IH, d) ; IR (solid)
3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344;

25 1294, 1224, 1162; MS 362.1 (M+fi)*

Example 6 {2- [2,4-Bis (trif luoromethyDphenylsulfanyl] -
quinazolin-4-yl}- (5-methyl-2H-pyrazol-3-yl) -amine
(IIa-6) : Prepared in a manner similar to the above
3 0 described Method E to afford a pale yellow solid, mp

>300®C; ^H NMR (DMSO) 5 1.98 (3H, s) , 5.37 (IH, s) , 7.50
(IH, t), 7.59 (2H, d), 7.84 (IH, d) , 8.32 (IH, s) , 8.40

-230-

(2H, s) , 8.66 (IH, d) , 10.73 (IH, br s) ; IR (solid)
1628, 1603, 1577, 1548, 1512, 1493, 1448, 1417, 1354,
1275, 1196, 1124; MS 470.1 (M+H)*

5 Example 7 12- {2-Chloropiienylsulfaiiyl) -qpiinazolixi-4-yl] -
(5-methyl-2H-pyxazol-3-yl) -amine (lla-7) : Prepared in a
manner similar to the above described Method E to afford
a pale yellow solid, mp 262-263»C; NMR (DMSO) 6 2 . 05
(3H, s) , 5.35 (IH, s) , 7.52 (2H, t) , 7.65 (2H, m) , 7.74
10 (IH, d), 7.83 (IH, t), 7.88 (IH, d) , 8.62 (IH, d) , 10.97
(IH, br s) ; IR (solid) 1621, 1603, 1569, 1544, 1491,
1448, 1400, 1376, 1336, 1288, 1208; MS 368.0 (M+H) *

Example 8 [2- (2,3-Dichlorophenylsulfanyl) -quinazolin-4-
15 yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIa-8) : Prepared in
a manner similar to the above described Method E to
afford a pale yellow solid, mp'>300«C; NMR (DMSO) 8
2.05 (3H, s), 5.34 (IH, s) , 7.50 (2H, m) , 7.60 (IH, d) ,
7.75 (IH, t) , 7.88 (2H, m) , 8.62 (IH, d) , 10.72 (IH, br
20 S) ; IR (Sblid) 1632, 1609, 1561, 1532, 1492, 1432, 1400,
1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M+H)*

Example 9 [2- (3-Chlorophenylsulfanyl) -quinazolin-4-yll -
( 5 -methyl -2H-pyrazol- 3 -yl)- amine (Ila-9) : Prepared in a

25 mzomer similar to the above described Method E to afford
a pale yellow solid, mp 248-249«»C; ^H NMR (DMSO) 6 2 . 05
(3H, s), 5.42 (IH, s), 7.55 (2H, m) , 7.66 (3H, m) , 7.81
(IH, s), 7.85 (IH, t), 8.62 (IH, d) , 11.10 (IH, br s) ; IR
(solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292,

30 1217, 1165; MS 368.0 (M+H)*

10

-231-

Example 10 [2- (l-Methyllmidazol-2-ylsulfanyl) -quinazolin-
4-yl]-{5-iiietliyl-2H-pyrazol-3-yl) -amine (IIa-10) : Prepared
in a manner similar to the above described Method E to
afford an off white solid, mp 255-256«»C; NMR (DMSO) 8
2.19 (3H, S) , 3.59 (IH, s)/-5.51 (IH, • s) , 7.18 (IH, s) ,
7.45 (IH, t) , 7.57 (IH, s) , 7.59 (IH, d) , 7.77 (IH, t) ,
8.57 (IH, d> , 10.57 (IH, s) , 12.13 (IH, br s) ; IR (solid)
1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333. 1292,
1278. 1211; MS 338.2 (M+H)*

Example 11 [2- (2-Hydroxyphenylsulfanyl) -quinazolin-4-yl] -
(5-ineth,yl-2H-pyrazol-3-yl) -amine (IIa-11) : Prepared in a

manner similar to the above described Method E to afford

a pale yellow solid, mp 273-27S«»C; NMR (DMSO) 8 2.06
15 {3H. s), 5.41 (IK, S), 6.99 (IH, t) , 7.07 (IH, d) , 7.50
(IH, t), 7.57-7.62 (2H, m) , 7.73 (IH, d) , 7.94 (IH. t) .

8.71 (IH. d). 10.29 (IH, br s) . 11.66 (IH, br s) ; IR
(solid) 1623, 1597, 1552. 1485. 1442, 1404, 1354, 1341,

1289. 1221, 1165; MS 350.1 (M+H)*

20

Example 12 [2- (2 , 4-Dif luorophenylsulf anyl) -qiiinazolin-4-
yl3 - ( 5 -methyl - 2H-pyrazol - 3 -yl ) - amine (Ila- 12 ) : Prepared
in a manner similar to the above described Method E to
afford a pale yellow solid, mp 256- 258 "C; ^H NMR (DMSO)
25 2.10 (3H, S) , 5.41 (IH, s) , 7.33 (IH, t) , 7.51-7.58 (2H,
m). 7.65 (IH, d), 7.82-7.91 (2H, m) , 8.63 (IH, d) , 11.06
(IH, br s); IR (solid) 1626, 1608, 1556, 1482, 1409,
1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 (M+H)*

30 Example 13 [2- (3, 4-Dimethoxyphenylsulfanyl) -quinazolin-4-
yl] - (5-methyl-2H-pyrazol-3-yl) -amine (lIa-13) : Prepared
in a manner similar to the above described Method E to
afford a pale yellow solid, mp 229-232«»C; ^H NMR (DMSO) 8

-232-

2.05 (3H, S), 3.70 (3H, s) , 3.85 (3H, s) , 5.39 (IH, s) ,
6.95 (IH, d), 7.30 (2H, d) , 7.60 (IH, t) , 7.77 (IH, d) ,
7.94 (IH, t), 8.72 (IH, d) , 11.66 (IH, br s) ; IR (solid)
1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254,
1237, 1218, 1161, 1157-; MS 394.1 (M+H)*

Example 14 [2- (3-Methylphenylsulf anyl) -quinazolin-4-yl] -
(5-inetliyl-2H-pyrazol-3-yl) -amine (lIa-14) : Prepared in a
manner similar to the above described Method E to afford
a pale yellow solid, mp 249-250 <>C; ^H NMR (DMSO) 8 2.06
(3H, S), 2.36 (3H, s) , 5.31 (IH, s) , 7.45 (2H, d) , 7.48-
7.58 (3H, m), 7.61 (IH, d) , 7.88 (lH, t), 8.68 (lH, d),
11.66 (IH, br S); IR (solid) 1617, 1587, 1558, 1496,
14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M+H)*

Example 15 12 - (2-Methoacyphenylsulf anyl) -quinazolin-4-yiI -
(5-methyl-2H-pyrazol-3-yl) -amine (IIa-15) : Prepared in a
manner similar to the above described Method E to afford
a pale yellow solid, mp 237-2390C; ^H NMR (DMSO) 5 2.07
(3H, s) , 3.71 (3H, S), 5.35 (IH, s) , 7.12 (IH, t) , 7.23
(IH, d) , 7.55 (IH, t), 7.60-7.67 (3H, m) , 7.87 (IH, t) ,
8.66 (IH, d), 11.20 (IH, br S) ; IR (solid) 1632, 1606,
1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS
364.1 (M+H)*

Example 16 [2- (2-Naphtlialenylsulf anyl) -quinazolin-4-yll -
(5-methyl-2H-pyrazol-3-yl) -amine (Ila-16) : Prepared in a
manner similar to the above described Method E to afford
a pale yellow solid, mp 267-270«»C; ^H NMR (DMSO) 5 2.05
(3H, S) , 5.09 (IH, s), 7.57 (IH, t) , 7.62-7.75 (4H, m) ,
7.90 (IH, t), 8.07 (3H, t) , 8.40 (IH, s) , 8.66 (IH, d) ,

-233-

11.28 (IH, br S) ; IR (solid) 1624, 1606, 1550, 1487,
1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M+H)*

Example 17 [2- (2, S-Dichlorophenylsulfanyl) -quinazolin-4-
5 yl] - (5-methyl-2H-pyrazol-3-yl) -amine {lla-17) : Prepared
in a manner similar to the above described Method E to
afford a pale brown solid, mp >300*C; NMR (DMSO) 6 2.11
(3H, s) , 5.49 (IH, s) , 7.49 (IH, t) , 7.59-7.67 (2H, m) ,
7.76 (2H, d) , 7.81 (IH, d) , 8.60 (IH, d) , 10.60 (IH, s) ;
10 IR (solid) 1618, 1599, 1565, 1533, 1486, 1424, 1401,

1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M+H)*

Example 18 [2- (3,4-Dichlorophenylsulfanyl) -quinazolin-4-
yll - (5-methyl-2H-pyrazol-3-yl) -amine (lIa-18) : Prepared

15 in a manner similar to the above described Method E to

afford a pale yellow solid, mp 268-272«>C; ^H NMR (DMSO) 8
2.11 (3H, S) , 5.47 (IH, s) , 7.56 (IH, t) , 7.68-7.72 (2H,
m) , 7.83 (2H, d), 7.88 (IH, t) , 8.05 (IH, d) , 8.66 (IH,
d) ; IR (solid) 1628, 1607, 1556, 1488, 1436, 14412, 1399,

20 1367, 1341, 1288, 1216, 1166; MS 402.0 (M+H)*

. . Example 19 £2- (Benzliiiidazol-2-ylsul£anyl).-quinazolin-4-
yll - (5-methyl-2H-pyrazpl-3-yl) -amine (IXa-19) : Prepared
in a maimer similar to the above described Method E to

25 afford a pale grey solid, mp 192-196'C; NMR (DMSO) 6
1.60 (3H, S) , 5.48 (IH, s) , 7.44 (2H, m) , 7.53 (IH, t)
7.69 (2H, d) , 7.76 (2H, m) , 7.85 (IH, t) , 8.64 (IH, d) ,
10.79 (IH, S) ; IR (solid) 1618, 1606, 1569, 1537, 1487,
1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 (M+H)*

30

Example 20 £2-^ (2-Aminophenylsulfanyl) -quinazolin-4-yl] -
( 5 -methyl -2H-pyrazol- 3 -yl) -amine (lla-20) : Prepared in a

-234-

manner similar to the above described Method E to afford
a bright yellow solid, mp 257-259«»C; NMR (DMSO) 8 2.11-
2.30 {3H, 2xbr s) , 6.10 (IH, br s) , 7.10-7.80 {7H, m) ,
8.60 (IH, br s), 9.80 (IH, br s) , 10.80 (IH, br s) ; IR
(solid) 1623, 1591, 1567, 1538, 1496, 1483, 1410, 1351

Example 21 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-
phenylsulfanyl-quinazolin-4-yl) -amine (IIa-21) : Prepared
in a manner similar to the above described Method E to
afford a yellow solid, mp 233-236«>C; NMR (DMSO) 5 0.89
(2H, d), 0.98 (2H, d), 1.67 {IH, m) , 5.48 (IH, s) , 7.54 -
7.73 (7H, m)., 7.8* (IH, t) , 8.68 (IH, d) , 11.60 (IH, br
S); IR (solid) 1629, 1606, 1577, 1546, 1509, 1484, 1438,
1413, 1370, 1291, 1219; MS 360.3 (M+H)*

Example 22 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-
methoxycarbonylphenylsiaf anyl ) -quinazolin- 4 -yl] - amine
(XXa-22) : Prepared in a meuiner similar to the above
described Method E to afford a white solid, rap 224-225«»C;
^H NMR (PUSO) 5 0.52 (2H, m) , 0.86 (2H, m) , 1.67 (IH, m) ,
3.86 (3H, S), 5.60 (IH, s) , 7.45 (IH, t) , 7.56 (IH, d) ,
7.66 (IH, t), 7.76 (IH, t) , 7.93 (IH, d) , 8.10 (IH, d) ,
8.18 (IH, S), 8.57 (IH, d) , 10.48 (IH, br s) , 12.07 (IH,
br s) ; IR (solid) 1724, 1617, 1593, 1567, 1526, 1478,
1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS
418.3 (M+H)*

Example 23 (5-Cyclopropyl-2H-pyrazol-3-yl) - C2- (3-
methylphenylsulfanyl) -quinazolin-4-yl] -amine (XIa-23) :

Prepared in a manner similar to the above described
Method E to afford a white solid, mp 241-243*C; ^H NMR
(DMSO) 8 0.55-0.63 (2H, m) , 1.87-1.97 (IH, m), 1.67-1.79

-235-

(IH, m), 2.35 {3H, S), 5.72 {IH, s) , 7.30-7.60 (6H, m) ,
7.68-7.78 (lH,m), 8.50-8.60 (IH, d) , 10.38 (IH, s) , 12.02
(IH, S) ; IR (solid) 1617, 1594, 1568, 1529, 1480, 1401,
1344, 1287, 1176, 758, 665,656; MS (M+H)*
5 .... ...

Example 24 (5-Cyclopropyl-2H-pyraj5ol-3-yl) - [2- (3-
metJicncyphenylsulfaxLyl) -quixiazolin-4-yl] -amine (Xla-24) :
Prepared in a manner similar to the above described
Method E to afford a white solid, rap 232-234«»C; NMR
10 (DMSO) 5 0.55-0.62 (2H, m) , 0.88-0.97 (2H, m) , 1.70-1.80
(IH, m), 3.79 (3H, S), 5.79 (IH, s) , 7.08 (IH, d) , 7.22-
7.29 (2H, m) , 7.40-7.50 (2H, m) , 7,60 (IH, d) , 7.79 (IH,
t) , 8.57 (IH, d) , 10.40 (IH, s) , 12.04 (IH, s) ; IR
(solid) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345,
15 1284, 1246, 1231, 1171, 1041, 1001, 969, 826, 761, 692,
667; MS (M+H)*

Example 25 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-
dimethoxyphenylsulfanyl) -quinazolin-4-yl] -amine (i:ia-25) :
Prepared in a manner similar to the above described
Method E to afford a white solid, nqp 250-252*C; ^H NMR
(DMSO) 5 0.54-0.60 (2H, m) , 0.83-0.91 (2H, m) , 1.68-1.77 %^
(IH, m), 3.79 (3H, s) , 3.85 (3H, s) , 5.79 (IH, s) , 7-10
(IH, d) , 7.20-7.26 (2H, m) , 7.45 (IH, t) , 7.57 (IH, d) ,
7.77 (IH, t) , 8.55 (IH, d) , 10.45 (IH, s), 12.04 (IH, m) ;
IR (solid) 1617, 1593, 1567, 1530, 1504, 1479, 1457,
1439, 1398, 1364, 1347, 1288, 1269, 1250, 1232, 1181,
1169, 1138, 1037, 1020, 997, 972, 882, 846, 804, 764,
750; MS (M+H)*

Example 26 [2- (3-Carboxyphenylsulfanyl) -qpiinazolin-4-yl] -
(5-cyclopropyl-2H-pyrazol-3-yl) -amine (IZa-26) : Prepared
from IZa-22 according to Method G to afford a yellow

20

25

30

-236-

solid, mp >300«»C; NMR (DMSO) S 0.53 (2H, d) , 0.86 (2H,
d) , 1.65 (IH, m) , 5.37 (IH, s) , 7.55 (IH, t) , 7.68 (IH,
t), 7.81 (IH, d) , 7.88 (IH, t) , 7.95 (IH, d) , 8.15 (IH,
d) , 8.15 (IH, s) , 8.71 (IH, d) , 11.32 (IH, br s) ; IR
5 (solid) 1702, 1626, 1609, 1559, 1490, 1412, 1355, 1293,
1222, 1170; MS 404.7(M+H)*

Example 27 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (naphtalen-
2-ylsulfanyl) -quinazolin-4-yl] -amine (Ila-27) : Prepared

10 in a manner similar to the above described Method E to
afford an off-white solid, nip 285-288 *»C; ^H NMR (r»lSO) 8
0.25 (2H, br s) , 0.52 (2K, br s) , 0.87 (IH, m) , 5.54 (IH,
br s), 7.42 - 7.77 (4H, m) , 8.00 (3H, m) , 8.30 (IH, br
s) , 8.56 (IH, br d) , 10.42 and 11.88 (IH, 2 x br s) ; IR

15 (solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287,
1240, 1216, 1167, 1158, 1142, 1128, 996, 965; MS
410.7{M+H)*

Example 28 ( 5 - Cydopropyl - 2H-pyrazol - 3 -yl )-[2-(2,4-
20 dif luorophenylsulf anyl) -qulnazolin-4-yl] -amine (ZIa-28} :
Prepared in a manner similar to the eJbove described
Method E to afford an off-white solid, rap 250-253 «»C; ^H
NMR (DMSO) 8 0.61 (2H, m) , 0.91 (2H, m) , 1.74 (IH, m) ,
5.67 (IH, m) , 7.24-7.28 (IH, m) , 7.44-7.48 {3H, m) , 7.53-
25 7.81 (2H, brm) , 8.55 (IH, m) , 10.47 and 12.10 (IH, 2 x br
s) ; IR (solid) 1614, 1598, 1565, 1525, 1479, 1423, 1398,
1366, 1345, 1285, 1267, 1243, 1213, 1168, 1143, 1114,
1026, 995, 968; MS 396.6 (M+H)*

30 Example 29 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2-

(naphthalen-2-ylsulfanyl) -5, 6, 7, 8-tetrahydroquinazolin-4-
yl] -amine (lla-29) : Prepared in a manner similar to the

-237-

above described Method P to afford a white solid, mp
244«»C; NMR (DMSO) 5 0.13 (2H,s), 0.45 (2H,s), 0.79 (IH,
S) , 1.73 (4H, s) , 2.42 (2H, s) , 2.58 (2H, s) , 5.28 (IH,
s) , 7.58 (2H, d) , 7.61 (2H, d) , 7.97 (3H, d), 8.23 (IH,
5s), 8.56 (IH, s) , 11.63 (IH, s) ; IR (solid) 1594, 1561,
1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657,
651; MS 414.7(M+H)*

Example 30 (5-Cyclopropyl-2H-pyra!8ol-3-yl) - [2- (2,3-
10 dichlorophenylsulfanyl) -quinazolin-4-yl] -amine (IIa-30) :.
Prepared in a manner similar to the above described
Method E to afford an off-white solid, 250-252°C; ^H
NMR (DMSO) 6 0.60 (2H, d) , 0.93 (2H, d) , 1.70 (IH, m) ,
5.54 (IH, s), 7.47 (2H, m) > 7.57 (IH, d) , 7.76 (IH, t) ,
15 7.86 (2H, d) , 8.57 (IH, d) , 10.48 (IH, s) , 12.04 (IH, s) ;
IR (solid) 1616, 1601, 1570, 1528, 1486, 1432, 1400,
1367, 1335, 1285, 1246, 1210, 1159, 1146, 1051, 1033,
1021, 99^7; MS 428.6(M+H)*

20 Example 31 [2- (B-CSilorophenylsulf anyl) -qainazolin-4-yl] -
(5-cyclcqpropyl-2H-pyrazol-3-yl) -amine (ZIa-31) : Prepared
in a manner similar to the above described Method E to
afford an off-white solid, mp 235-23 8 «»C; ^H NMR (DMSO) 6
0.58 (2H, d) , 0.92 (2H, d) , 1.75 (IH, m) , 5.71 (IH, s) ,
25 7.44 (IH, t), 7.50 - 7.63 (4H, m) , 7.73 (IH, s) , 7.75

(IH, t) , 8.57 (IH, d) , 10.46 (IH, s) , 12.08 (IH, s) ; IR
(solid) 1616, 1593, 1562,. 1528, 1479, 1456, 1406, 1367,
1343, 1286, 1244, 1216, 1176, 1067, 1051, 997; MS
394.7 (M+H)*

30

Example 32 [2- (2-Chlorophenylsulfanyl) -quinazolia-4-yl] -
( 5 - cydopropyl - 2H-pyrazol - 3 -yl ) - amine (Ila - 3 2 ) : Prepared

-238-

in a m^Maer similar to the above described Method E to
afford an off-white solid, mp 255-257»C; KMR (DMSO) 5
0.59 (2H, d), 0.91 (2H, d) , 1.71 (IH, m) , 5.62 (IH, s) ,
7.45 (2H, m), 7.57 (IH, m) , 7.69 (IH, d) , 7.75 (IH, t) ,
5 T.85 (IH, d), 8.56 (IH, d) , 10.43 (IH, s) , 12.03 (IH, s) ;
IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398,
1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054,
1030, 997; MS 394.7(M+H)*

10 Example 33 (5-Cyclopropyl-2H-pyraaol-3-yl) - [2- (3,4-

dimethylphenylsulfanyl) -<3uinazolin-4-yl] -amine (IIa-33) :

Prepared in a manner similar to the above described
Method E to afford an off-white solid, mp 255-256'C;
NMR (DMSO) 6 0.56 (2H, m) , 0.90 (2H, m) , 1.67 (IH, m) ,
15 2.26 and 2.29 (6H, 2 x s) , 5.75 (IH, br s) , 7.26 (IH, m) ,
7.35-7.55 (4H, m) , 7.74 (IH, m) , 8.54 (IH, br s) , 10.44
and 12.06 (2H, 2 x br s) ,- IR (solid) 1617, 1596, 1569,
1526, 1479, 1459, ±404, 1366, 1343, 1287, 1243. 1218,
1167, 1145, 1017, 9S»6, 966; MS 388 . 3 (M+H) *

20

Example 34 12- (Benzimidazol-2-ylsxilf anyl) -quinazolin-4-
yl] - (5-cyclopr«^yl-2H-pyrazol-3-yl) -aaaine (IIa-34) :
Prepared in a maimer similar to the above described
Method E to afford an off-white solid, mp 201-203«»C;
25 NMR (DMSO) 5 0.44 (2H, m) , 0.71 (2H, m) , 1.17 (IH, m) ,

5.72 (IH, m), 7.23 (2H, m) , 7.51-7.81 (5H, m) , 8.59. (IH,
m) , 10.59, 12.06 and 13.17 (3H, 3 x br s) ; IR (solid)
1617, 1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290,
1273, 1209, 1168, 1024, 1010, 965; MS 400.2 (M+H)*

30

Example 35 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-
methoxycaurbonylphenylsulf anyl) -qulnazolin-4-yl] -amine

10

-239-

(IZa-35) : Prepared in a manner similar to the shav&
described Method E to afford an off-white solid, mp 245-
246<>C; NMR (DMSO) 5 0.47 (2H, br s) , 0.80 (2H, br s) ,
1.62 (IH, m) , 3.85 (3H, s) , 5.69 (IH, br s) , 7.46 (IH,
m) , 7.58 (IH, m) , 7.76-7.81 (3H, m) , 8.02-8.05 (2H, m) ,
8.57 (IH, m) , 10.48 and 12.11 (2H, 2 x br s) ; IR (solid)
1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435,
1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS
418.2 (M+H)*

Example 36 [2- {4-Aeetamido-phenylsulf anyl) -quinazolin-4-
yl] - {5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-36) :
Prepared in a manner similar to the above described
Method E to afford an off-white solid, mp 23 9-2410C;

15 NMR (DMSQ) 5 0.57 {2H, m) , 0.83 (2H, m) , 1.69 (IH, m) ,
2.02 (3H, S) , 5.73 (IH, br s) , 7.41 (IH, m) , 7.53-7.57
(3H, m), 7.73-7.75 (3H, m), 8.54 (IH, m) , 10.18, 10.39
and 11.98 (3H, 3 x br s) ; IR (solid) 1665, 1618, 1607,
1586, 1572, 1564, 1529, 1482, 1387, 1343, 1320, 1287,

20 1243, 1221, 1162, 1005, 968; MS 417.2 (M+H)*

Example 37 (5-Cyclppropyl-2H-pyrazol-3-yl) - [2-
(naphthalen-l-ylsulf anyl) -quinazolin-4-yl] -amine (Ila-
37) : Prepared in a manner similar to the above described

25 Method E to afford an off-white solid, mp 271-273«>C; ^H
NMR (DMSO) 5 0.46-0.47 (2H, m) , 0.87-0.89 (2H, m) , 1.57
(IH, m) , 5.01 (IH, m) , 7.42 (IH, m) , 7.52-7.54 (3H, m) ,
7.64 (IH, m) , 7.75 (IH, m) , 7.98 (IH, m) , 8.06 (IH, m) ,
8.17 (IH, m) , 8.28 (IH, m) , 8.50 (IH, m) , 10.29 (IH, br

30 S) , 11.84 (IH, br s) ; IR (solid) 1615, 1592, 1567, 1528,
1483, 1401, 1362, .1343, 1285, 1242, 1219, 1173, 998, 963;
MS- 410.2 (M+H)*

-240-

Example 38 [2 - ( 4 - Acetamidophenylsulf smyl) - cpiinazolin- 4 -
yll - (5-methyl-2H-pyrazol-3-yl) -amiae (IZa-38) : Prepared
in a manner similar to the above described Method E to
afford an white solid, mp 268-271-C; NMR (DMSO) 5 2.02
(3H, S) , 2.09 {3H, S), 5.56 (IH, s) , 7.40 (IH, t) , 7.55
(3H, m), 7.75 (3H, d) , 8.55 (IH, d) , 10.21 (IH, s) , 10.40
(IH, s) , 12.03 (IH, s) ; IR (solid) 1S62, 1620, 1599,
1572, 1531, 1438 i 1397, 1370, 1358, 1341, 1323, 1312,
1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391.2 (M+H)*

Example 39 [2- (4-Methanesulfonylamino-phenylsulfanyl) -
quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (11a-

39) : Prepared in a manner similar to the above described
Method E to afford an off-white solid, mp 219-222«'C;
NMR (DMSO) 5 2.15 (3H, s) , 2.61 (3H, s) , 5.84 (IH, s) ,
6.91 (2H, d), 7.22 (2H; d) , 7.36 (IH, s) , 7.52 (IH, d) ,
7.69 (IH, s), 8.53 (IH, d) , 10.31 (IH, s) , 11.96 (IH, s) ;
IR (solid) 1621, 1602, 1584, 1567, 1528, 1486, 1351,
1287, 1253, 1207, 1179, 1102, 1091, 983; MS 427.0 (M+H)*

Example 40 [2 - (4 -Acetamidophenylsulf anyl) -7 -methoxy-
quinazolin-4-yll - (5-methyi-2H-pyrazol-3-yl) -amine (Ila-

40) : Prepared in a manner similar to the above described
Method E to afford a white solid, rap 291-293-C; NMR
(DMSO) 5 2.01 (3H, S), 2.09 {3H, s) , 3.87 (3H, s) , 5.55
(IH, S), 6.96 (IH, S) , 6.99 (IH, d) , 7.55 (2H, d) , 7.73
(2H, d) , 8.45 (IH, d), 10.21 (IH, s) , 10.23 (IH, s) ,
11.99 (IH, s); IR (solid) ; MS 421.2 (M+H)*

Example 41 [2- (4 -Acetamidophenylsulf anyl) -8- (3-morpholin-
4-yl-propoxy) -quinazolin-4-yl] - (5-methyl-2H-ipyrazol-3-

-241-

yl) -amine (ZIa-41) : Prepared in a manner similar to the
above described Method E to afford a white solid, rap 262-
264«»C; *H NMR (DMSO) 8 1.94 (2H, quint.) , 2.03 (3H, s) ,
2.09 (3H, S) , 2.38 (4H, s) , 2.45 (2H, t) , 3.58 (4H, s) ,
5 4.11 (2H, t) , 5.60 (1H, S), 7.24 (IH, d) , 7.30 (IH, t) ,
7.57 (2H, d) , 7.73 (2H, d) , 8.07 <1H, d) , 10.20 (IH, s) ,
10.24 (IH, s), 12.02 (IH, br s) ; IR (solid) 3245, 3045,
2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468, 1391,
1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 ; MS
10 534.4 (M+H)*

Example 42 [2- (4-Methoxycarbonylplienylsulf anyl) -
quinazolin-4-yl] - (5-methyl-2flr-pyrazol-3-yl) -amine (Ila-
42) : Prepared in a maimer similar to the above described

15 Method E to afford an off-white solid, mp 257-260'>C;

NMR (DMSO) 5 1.95 (3H, s) , 3.89 (3H, s) , 5.51 (IH, br s) ,
7.39 (IH, br s) , 7.51 (IH, br s) , 7.70 (IH, br s) , 7.81
(2H, d) , 8.04 (2H, d) , 8.51 (IH, br s) , 10.48 (IH, br s) ,
12.03 (IH, brs); IR (solid) 1718, 1618, 1599, 1568,

20 1531, 1481, 1434, 1395, 1362, 1342, 1286, 1247, 1216,
1156, 1116, 1018, 1003, 968 ; MS 392.2(M+H)*

■ <o

Example 43 [2- (4-Carbo3cyphenylsulf auiyl) -quinazolin-4-yl] -
(S-msthyl-2H-pyrazol-3-yl) -amine (IIa-43) : Prepared in a
25 manner similar to the above described Method E to afford
an off-white solid, rap 263-265»C; ^H NMR (DMSO) 8 1*98
(3H, s), 5.50 (IH, S),. 7.46 (IH, t) , 7.60 (IH, d) , 7.78
(3H, m) , 8.02 (2H, d) , 8.58 (IH, d) , 10.58 (IH, s) , 12.50
(IH, br s) ; IR (solid) 1623, 1605, 1574, 1560, 1533,
30 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131,
1088, 1018; MS 378.2 (M+H)*

-242-

Example 44 [2- (4-Acetamidopheny-lsulf anyl) -B-methoacy-
qulnazolln-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ila-
44) : Prepared in a manner similar to the above described
Method E to afford an off-white solid/ 247-249«»C;^H
5 NMR (DMSO) 1.99^ (3H, s)-, 2.10 {3H, s) , 3.93 (3H, s) , 5,40
(IH, s) , 7.31 (IH, d), 7.38 (IH, t) , 7.57 (2H, d) , 7.76
(2H, d) , 8.11 (IH, d), 10.28 (IH, s) , 10.61 (IH, s) ,
12.11 (IH, br s) ; IR (solid) 3234, 3052, 2938, 1673,
1618, 1591, 1536, 1481, 1459, 1390, 1372, 1345, 1317,
10 1267, 1249, 1158, 1058, 985, 830; MS 421.2(M+H)*

o .

Example 45 [2- (4-Acetamidophenylsulf anyl) -7- (3-morpholin-
4-yl-propoxy) -c[uxnazolin-4-yl] - (5-methyl-2H-pyrazol-3-
yl) -amine (lIa-45) : Prepared from IIa-74 according to

15 Method I to afford an off-white solid, mp 153°C (dec); ^H
NMR (EWISO) 5 2.02 (3H, s) , 2.09 (3H, s) , 2.29 (2H,
quint.), 3.16 (2H, m) , 3.36 (4H,m) , 3.57 (4H, m), 4.11
(2H, m) , 5.58 (IH, s)-, 7.22-7.29 (2H, m) , 7.55 (2H, d) ,
7.76 (2H, d), 8.07 (IH, d) , 10.26 (IH, br s) , 10.35 (IH,

20 S) , 12.06 (IH, br s);. IR (solid) 1673, 1614, 1591, 1532,
1486, 1391, 1336, 1254, 1109, 1063, 995; MS 534.2 (M+H)*

c>

Example 46 [2- (4-Broaiiophenylsulf amyl) -quinazolin-4-yl] -
(5-methyl-2'H-pyrazol-3-yl) -amine (XXa-46} : Prepared in a

25 manner similar to the above described Method E to afford
an off-white solid. Tap >300«»C; ^H NMR (DMSO) 6 2.15 (3H,
s) , 5.63 (IH, br s) , 7.44 (IH, m) , 7.55-7.62 (3H, m) ,
7.69-7.77 (3H, m) , 8.56 (IH, m) , 10.47 and 12.12 (2H, 2
X br s) ; iR (solid) 1615, 1597, 1565, 1525, 1478, 1396,

30 1362, 1339, 1285, 1218, 1158, 1034, 1009, 967 ; MS
412.1/414.1 (M+H)*

-243-

Example 47 [2- (3-Bramopheaylsulf anyl) -quina2oliii-4-yl] -
( 5 -methyl -2H-pyrazol- 3 -yl) -amine (lla-47) : Prepared in a
manner similar to the abofve described Method E to afford
an off-white solid, mp 280-281<»C; NMR (DMSO) 8 2.12
(3H, s) , 5.54 (IH, br S) , 7.46 (IH, m)V 7.55-7.68 (3H,
m), 7.7S-7.88 (3H, m) , 8.81 (IH, m) , 10.49 and 12.11
(2H, 2 X br s) ; IR (solid) 1617, 1600, 1567, 1530, 1483,
139&, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005,
967; MS 412 . 2/414 . 2 (M+H) *

Example 48 [2- (4-Isopropanesulfonylamino-phenylsulf anyl) ■
quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ila-

48) : Prepared in a manner similar to the above described
Method E to afford a white solid, mp 294-297«>C; NMR
(DMSO) 5 1.26 (6H, d) , 2.13 (3H, s) , 5.75 (IH, s) , 7.34
(2H, d), 7.41 (IH, t), 7.54 (IH, d) , 7.59 (2H, d) , 7.73
(IH, t) , a. 53 (IH, d), 10.16 (IH,. s), 10.42 (IH, s) ,
12.07 (IH, br s); IR (solid) 1613, 1593, 1560, 1530,
1482, 1384, 1364, 1346, 1320, 1290, 1265, 1243, 1216,
1169, 1141, 1084, 1056, 1019, 999, 969, 916; MS

455.2 (M+H)*

Example 49 [2- (4-Isdbutyrylamino-phenylsulf anyl) -
quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ila-

49) : prepared in a manner similar to the above described
Method E to afford an off-white solid, mp 285-287«»C; ^H
NMR (DMSO) 8 1.12-1.13 (6H, m), 1.99 (3H, s) , 2.64 (IH,
m), 5.52 (IH, br s), 7.41 (IH, m) , 7.54-7.57 (3H, m) ,
7.72-7.77 (3H, m) , 8.54 (IH, m) , 10.12, 10.41 and 12 . 04
(3H, 3 X br s) ; IR (solid) 1704, 1680, 1617, 1590, 1566,
1516, 1481, 1395, 1358, 1341, 1286, 1247, 1214, 1155,
1052,. 1032, 1006, 969; MS 419.3(M+H)*

-244-

Exanrple 50 ( 5 -Methyl - 2H-pyrazol - 3 -yl ) - [2 - ( 4 -
propionylamino-phenylsulf anyl) -quinazolin-4-yl] -amine
(IXa-50) : Prepared in a manner similar to the above
5 described Method E to afford an off-white solid, mp 281-
282'»C; NMR (DMSO) 6 1.11-1.13 (3H, m) , 1.98 (3H, s) ,
2.33 (2H, m) , 5.51 (IH, br s) , 7.41 (IH, m) , 7.55-7.57
(3H, m) , 7.71-7.78 (3H, m) , 8.54 (IH, m) , 10.11, 10.41
and 12.04 (3H, 3 x br s) ; IR (solid) 1654, 1621, 1599,
10 1571, 1527, 1476, 1398, 1358, 1341, 1286, 1244, 1216,
1155, 1006, 969; MS 405.3 (M+H)*

Example 51 [2- (4-cyclopropanecarbonylamino-
phenylsulfanyl) -quina2olin-4-yll - (5-methyl-2H-pyrazol-3-

15 yl) -amine (IIa-51) : Prepared in a manner similar to the

above described Method E to afford an off-white solid, mp
300-303'C; NMR (DMSO) 5 0 . 82-0 . 84 (4H, m) , 1.83 (IH,
m) , 2.01 (3H, s), 5.55 (IH, br s) , 7.39-7.41 (2H, m) ,
7.53-7.57 (2H, m), 7.72-7.77 (2H, m) , 8.53-8.55 (2H, m) ,

20 10.40, 10.46 and 12.03 (3H, 3 x br s) ; IR (solid) 1664,
1614, 1591, 1560, 1526, 1480, 1432, 1390, 1344, 1288,
1240, 1194, 1177, 1152, 997; MS 417.2 (M+H)*

Example 52 [2- (4-Acetamido-phenylsulfanyl) -8-.
25 h.ydxoxyquixiazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine
(XIa-52) : tan solid, mp 258-259«»C; NMR (DMSO) 8 1.99
(3H, s) , 2.09 (3H, s) , 5.45. (IH, s) , 7.10 (IH, d) , 7.22
(IH, t), 7.57 (2H, d), 7.75 (2H, d) , 7.95 (IH, d) , 9.35
(IH, s) , 10.22 (IH, S), 10.26 (IH, s) , 12.00 (IH, br s) ;
30 IR (solid) 3295, 3272, 3181, 3109, 1654, 1591, 1527,

1482, 1459, 1386, 1368, 1314, 1268, 1141, 1077, 991, 814;
MS 407.2 (M+H)*

-245-

Example 53 [2- (4-Acetamido-phenylsulfanyl) -7-
nitroguinazoliii-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine
(Xla-53) : Prepared in a manner similar to the above
5 described Method- E to afford a yellow solid; NMR (DMSO)
6 2,02 (3H, s) , 2.09 (3H, s) , 5.54 (IH, s) , 7.58 (2H, d) ,
7.75 (2H, d) , 8.08 (IH, d) , 8.22 (IH, s), 8-80 (IH, d) ,
10.24 (IH, s) , 10.85 (IH, s) , 12-15 (IH, s) ; IR (solid);
MS 436.2 (M+H)*

10

Example 54 (5-Methyl-2H-pyrazol-3-yl> -{2- [4- (prppane-1- ^
sulfonylaaaino) -phenylsulf anyl] -qiiinazol±n-4-yl} -amine
{I la- 54) : Prepared in a manner similar to the above
described Method E to afford a white solid, mp 272-273«>C;

15 ^H NMR (I»«SO)- 8 0.95 (3H, t) , 1.71 (2H, m) , 2.13 (3H,s),
3.18 (2H, t) , 5.70 (IH, s) , 7.31 (2H, d) , 7.41 (IH, t) ,
7.52 (IH, d), 7.58 (IH, d) , 7.73 (IH, t) , 8.55 (IH, d) ,
10.16 (IH, s) , 10.42 (IH, s) , 12.07 (IH, s) ; IR (solid)
1615, 1594, 1563, 1530, 1481, 1389, 1362, 1346, 1325,

20 1291, 1245, 1147, 969; MS 455.2 (M+H)*

Example 55 [2- (4-Ethylsulf onylamino-phenylsulf anyl) - ^

quinazolin- 4 -yl] - ( 5 -methyl - 2H-pyrazol - 3 -yl ) - amine
(lIa-55) : Prepared in a manner similar to the above
25 described Method E to afford an off-white solid, mp 279-

280»C; NMR (DMSO) 8 1.28 (3H, t) , 2.19 (3H,s) , 3.25
(2H, m), 5.76 (IH, s), 7.36 (2H, d) , 7.48 (IH, t) , 7.53
(IH, d), 7.65 (IH, d), 7.80 (IH, t) , 8.61 (IH, d) , 10.23
(IH, s), 10.49 (IH, s), 12.13 (IH, s) ; IR (solid) 1615,
30 1597, 1564,. 1532, 1506, 1485, 1455, 1388, 1361, 1347,

1323, 1294, 1218, 1150, 1033, 1016, 998, 968, 918; MS

441.2(M+H)*

-246-

Example 56 [2- (4-AcetaiBido-phenylsulf anyl) -7-
hydro3^aminoquinazolin-4-yl] - (5-metliyl-2H-pyrazol-3-yl) -
amine (Ila-56) : Prepared from IIa-53 according to Method
J to afford a yellow solid; NMR (DMSO) 5 1.97 (3H, s) ,
2.11 (3H, S), 5.19 (IH, S), 6.88-6.91 (2H, m) , 7.65 (2H,
d), 7.85 (2H, d), 8.44 (IH, d) , 9.27 (IH, br s) , 10.49
(IH, s) , 11.38 (IH, s). 14.58 (IH, br s) ; IR (solid); MS
422.2 (M+H)*

Example 57 [2- (4-Isobutanecarbonylaiaino-phenylsulf anyl) -
quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ila-
57) : Prepared in a manner similar to the above described
Method E to afford a white solid, mp 281-282°C; NMR
(DMSO) 6 0.95-0.97 (6H, m) , 2.00 (3H, s), 2.12 (IH, m) ,
2.23-2.25 (2H, m) , 5.56 (IH, s) , 7.41 (IH, m) , 7.54-7.57
{3H, m) , 7.72-7.78 (3H, m) , 8.54 (IH, m) , 10.14, 10.41
and 12.03. (3H, 3 x br s) ; IR (solid) 1737, 1658, 1618,
1599, 1566, 1530, 1483, 1432, 1394, 1364, 1343, 1313,
1287, 1242, 1216, 1167, 1151, j.003, 967; MS 433.2 (M+H)*

Example 58 [2- (4-tert-Butoxycarbonylamino-
phenylsulfanyl) -quinazol±n-4-yll - (5-methyl-2H-pyrazol-3-
yl) -amine (lla-58) : Prepared in a manner similar to the
above described Method E to afford a white solid, mp 243
246»C; NMR (DMSO) 6 1.50 (9H, s) , 1.97 (3H,s), 5.40
(IH, S), 7.07 (2H,. br S), 7.36 (IH, br S), 7.47 (2H, d) ,
7.58 (2H, d), 8.12 (IH, br s) , 9.58 (IH, s) , 11.24 (IH,
br s) ; IR (solid) 1701, 1593, 1559, 1515, 1482, 1396,
1365, 1346, 1308, 1288, 1237, 1154, 1051, 1020, 969; MS
449.2 (M+H)*

-247-

Example 59 [2- (4-Acetainido-phenylsulfaxiyl) -7-
aiiiinoquinazolln-4-yl] - (5-niethyl-2H-pyrazol-3-yl) -amine
(ZIa-59) : Prepared from IIa-53 according to Method K to
afford an off-white solid, mp 264-265 'C; NMR (DMSO) 5
5 1.9^9 (3H, S) , 2.09 (IH, s), 5.53 (IH, s) , 5.97 (2H, s) ,
6.47 (IH, s) , 6.68 (IH, d) , 7.52 (2H, d) , 7.71 {2H, d) ,
8. IS (IH, d) , 9.83 (IH, br s) , 10.19 (IH, s) , 10.87 (IH,
br s) ; IR (solid) ; MS 406.2 (M+H)*

10 Example 60 (5-Metliyl-2H-pyrazol-3-yl) -{2- [4- (2-niorpholin-
4-yl-acetylainino) -phenylsulfanyl] -quinazolin-4-yl} -amine
(ZIa-60) : Prepared in a manner similar to the above
described Method E to afford an off-white solid, mp 266-
267 «»C; ^H NMR (DMSO) 5 2.03 (3H, s) , 2.57 (4H, m) , 3.23

15 (2H,S), 3.69 (4H, m) , 5.58 (IH, s) , 7.40 (IH, t) , 7.55-
7.62 (3H, m) , 7.75 (IH, t) , 7.80 (2H, d ), 8.54 (IH, d) ,
10.02 (IH, S) , 10.41 (IH, s), 12.03 (lH,s) ; IR (solid)
1686, 1598, 1564, 1533, 1515, 1484, 1387, 1362, 1348,
129-1, 1113, 868, 801, 773; MS 476.4 (M+H)*

20

Example 61 (5-Cycloprpyl-2Hrpyrazol-3-yl) - [2- (4-
methylsulfonylamino-phenylsulfanyl) -qulnazolin-4-yll -
amine (IXa-61) : Prepared in a manner similar to the above
described Method E to afford a white solid, mp 235-2380C;

25 ^H NMR (DMSO) 6 0.61 (2H, s) , 0.92 (2H, d) , 1.82 (IH, br
S), 2.98 (3H,s), 5.90 (IH, s) , 7.23 (2H, d), 7.41 (IH,
t), 7.54 (3H, m), 7.72 (IH, t), 8.55 (IH, d) , 10.16 (IH,
brs), 10.38 (IH, s) , 11.99 (IH, s) ; IR (solid) 1621,
1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290,

30 1232, 1143, 1113, 985, 972; MS 453.3 (M+H)*

-248-

Bxample 62 [2- (4-Amino-phenylsulf anyl) -quinazolin-4-yl] -
( 5 -methyl -2H-pyrazol- 3 -yl) -amine (ila-62) : Prepared in a

manner similar to the above described Method E to afford

an off-white solid, tnp >300«»C; NMR (DMSO) 5 2.16 (3H,
5 S) , 5.58 (IH, s), 6.78 (2H,. d) , 7.36 (2H, d), 7.64 (2H,

m) , 7.94 (IH, t) , 8.74 (IH, d) , li.82 (IH, br s) ; IR
(solid) 1615, 1591, 1561, .1532, 1495, 1480, 1387, 1363,

1344, 1288, 1244, 1148, 966; MS 349 . 2 (M+H) *

10 Example 63 [2- (4-Acetamido-phenylsulf anyl) -quinazolin-4-
(3 yl] - {2H-pyrazol-3-yl) -amine (IIa-63) : Prepared in a

manner similar to the above described Method E to afford
a white solid, NMR (DMSO) 5 2.11 (3H, s) , 5.93 (IH, s) ,
7.31-7.68 (8H, m) , 8.54 (IH, s) , 10.17 (IH, s) , 10.54

15 (IH, S) . 12.38 (IH, S) ; IR (solid); MS 377.4(M+H)*

Example 64 (5-Methyl-2H-pyrazol-3-yl) -.{2- [4- (4-morpholin-
4-yl-butyrylamino) -phenylsulfanyl] -quinazolin-4-yl}-amine
(Ila-64) : Prepared in a manner similar to the above
20 described Method E to afford a white solid, tap 240-243»C;
*H MMR (DMSO) 5 1.77 (2H, m) , 2.00 (3H, s) , 2.31-2.38 (8H,
m) , 3.57 (4H, m) , 5.54 (IH, s) , 7.39-7.76 <7H, m) , 8.53
(IH, br m) , 10.15 .(IH, s) , 10.41 (IH, s), 12.00 (IH, br
S) ; IR (solid); MS 504.3 (M+H)*

( )

25

30

Example 65 (5-Methyl-2H-pyrazol-3-yl) -{2- £4- (2-morpholin-
4-yl-ethylcarbamoyl) -phenylsulfanyl] -quinazoiin-4-yl}-
amine (IIa-65) : Prepared in a manner similar to the above
described Method E to afford a white solid, mp 246-248'»C;
^H NMR (DMSO) 5 1.97 (3H, s) , 2.43 (4H, br s), 3.30 (2H,
s) , 3.42 (2H, m) , 3.58 (4H, br s) , 5.52 (IH, s) , 7.43
(IH, t) , 7.55 (IH, d) , 7.76 (3H, m) , 7.97 (2H, d) , 8.56

15

-24&-

(2H, m) , 10.45 (IH, s) , 12.05 (IH, br s) ; IR (solid)
1637, 1618, 1596, 1568, 1530, 1484, 1396, 1362, 1343,
1286, 1247, 1216, 1159, 1116, 1006, 967; MS' 490 . 3 (M+H) *

Example 66 - [8-Metlioxy-2- (4-metiiylsulf onylamino-
phenylsulfanyl) -quinazoliii-4-yl] - (5-methyl-2H-pyrazol-3-
yl) -amine (IIa-66) : Prepared in a manner similar to the
above described Method E to afford an off-white solid, mp
275-277 »C; NMR (DMSO) 5 2 . 10 (3H, s) , 3.07 (3H, s) ,
3.89 (3H, s), 5.58 (IH, s) , 7-24 (IH, d) , 7.26-7.36 (3H,
m), 7.60 (2H, d), 8.07 (IH, d) , 10.13 (IH, s) , 11.26
(IH, s), 12.03 (IH, S); IR (solid) 3379, 1622, 1595,
1531, 1481, 1467, 1344, 1326, 1271, 1248, 1143, 1061,
993, 975, 924, 829; MS 457.2(M+H)*

Example 67 {2- [4- (2-Dlmethylanilno-ethylcarbanioyl) -
phenylsulfanyl] -quinazolin-4-yl}- (5-inethyl-2H-pyrazol-3-
yl) -amine (lla-67) : Prepared in a manner similar to the
above described Method E to afford a white solid, 192-
20 193<»C; *H NMR (DMSO) 5 1.99 (3H, s) , 2.20 (6H,s), 2.42

(2H, t), 3.40 (2H, q), 5.56 (IH, s) , 7.43 (IH, t) , 7.57
(IH, d), 7.77 (3H, m) , 7.92 (2H, d) , 8.56 (2H, m) , 10.44
(IH, s) , 12.04 (IH, br s) ; IR (solid) 1650, 1618, 1593,
1561, 1525, 1481, 1419, 1395, 1361, 1337, 1287, 1247,
25 1214, 1165, 1004, 969; MS 448.3 (M+H)*

Example 68 {2- [4- (2-Dlmethylamino-acetylamino) -
phenylsulfanyll -quinazolin-4-yl}- (5-methyl-2H-pyrazol-3-
yl) -amine (lIa-68) : Prepared in a manner similar to the
3 0 above described Method E to afford a white solid, mp 241-
243<»C; ^H NMR (DMSO) 5 2.00 (3H, s) , 2.33 (6H, s) , 3.14
(2H, s), 5.60 (IH, S), 7.40 (IH, t) , 7.58 (3H, m ), 7.77

-250-

. (IH, t ), 7.76 (2H, d), 8.58 (IH, d) , 10.04 (IH, s) ,
10.42 (IH, s), 11.&9 (IH, s) . ; IR (solid) 1707, 1617,
1601, 1571, 1509, 1485, 1420, 1397, 1365, 1304, 1290,
1243, 1215, 1161, 970, 847, 813, 765, 716, 683, 656; MS
5 434.3 (M+H)*

Example 69 [8-Hydroxy-2- (4-iiiethylsulfonylamino-
phenylsulfanyl) -quinazolin-4-yl] - (5-meth,yl-2H-pyrazol-3-
yl) -amine (IIa-69) : pale green solid, mp 291-293»C; NMR
.10 (DMSO) 5 2.10 (3H, s) , 3.09 {3H, s) , 5.57 (IH, s) , 7.11
O (IH, d), 7.24 (IH, t), 7.31 (2H, d) , 7.62 (2H, d) , 7.96

(IH, d>, 9.32 (IH, s), 10.16 (IH, s) , 11.28 (IH, s) ,
12.02 (IH, s) ; IR (solid) 3256, 1596, 1531, 1460, 1392,
1317, 1334, 1296, 1267, 1146, 993, 968, 931, 824; MS
15 443.2 (M+H)*

Example 70 {2- [4- (3-Dimethylaiaino-propylcarbainoyl) -
phenyl sulfanyl 3 -quinazolin-4-yl}- (5-metliyl-2H-pyrazol-3-
yl) -amine (lIa-70) : Prepared in a mani.er similar to the
20 above described Method E to afford a pink solid, mp 210-
213«»C; NMR (DMSO) 5 1.48 (2H, m) , 2.01 (3H, s), 2.24
O (6H,S), 2.38 (2H, br s) , 2.93 (2H, s) , 5.57 (IH, s) , 7.48

(IH, t), 7.62 (IH, d), 7.80 (3H, m) , 8.02 (2H, d) , 8.61
(IH, d) 8.74 (IH, S), 10.50 (IH, s), 12.15 (IH, br s) ; IR
25 (solid) 1682, 1618, 1595, 1567, 1528, 1484, 1400, 1361,
1344, 1285, 1247, 1219, 1172, 1084, 1006, 969; MS
462.3 (M+H)*

Example 71 {2- [4- (3-Dimethylamino-propionylam±no) -
30 phenylsulfanyl] -quinazolin-4-yl}- (5-methyl-2H-pyrazol-3-
yl) -amine (IIa-71) : Prepared in a manner similar to the
above described Method E to afford an off-white solid, mp
280"»C (dec.);^HNMR (DMSO) 82.09 (3H, s) , 2.60 (6H, s) ,

-251-

2.33 {2H, m), 3.10 (2H, m) , 5.64 (IH, 8), 7.47 (IH, t) ,
7.59-7.70 (3H, m) , 7.80-7.87 (3H, m) , 8.61 (IH, d) , 10.47
(IH, s) , 10.48 (IH, S) , 12.15 (IH, s) . ; IR (solid) 1670,
1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364,
5 1348-, 1286, 1178, 1162, 764; MS 448.4{M+H)*

Example 72 [2- (4-Acetainido-plienylsulfanyl) -S-methoacy-
quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) -amine
(Ila-72) : Prepared in a meumer similar to the above

10 described Method E to afford an off-white solid, mp 265-

268<»C; NMR (DMSO) 5 0.49-0.56 .(2H, m) , 0.79-0.83 (2H, ^
m), 1-55-1.70 (IH, m) , 2.06 (3H, s) , 3.89 (3H, s) , 5.61
(IH, s) , 7.25 (IH, d) , 7.33 (IH, t) , 7.56 (2H, d) , 7 . 74
(2H, d) , 8.07 (IH, d) , 10.17 (IH, s) , 10.26 (IH, s) ,

15 11.94 (IH, br s) ; IR (solid) 3250, 1671, 1617, 1595,
1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160, 1131,
1071, 1011, 984, 869, 815; MS 447.4 (M+H)*

Example 75- [2- (4-Acetamidophenylsulf anyl) -8- (3-
20 dimethylamino-propoxy) -qpiinazolin-4-yl] - ( 5 -methyl - 2H-
pyrazol-3-yl) -amine (XIa-73) : Prepared in a manner
similar to the above described Method B to afford an off- O
white solid, mp 170-172«'C; NMR (DMSO) 5 1.91 {2H,
quint.), 2.03 (3H, s) , 2.09 (3H, s) , 2.17 (6H, s) , 2.40
25 (2H, t), 4.10 (2H, t) , 5.59 (IH, s) , 7.23 (IH, d) , 7.30'
(IH, t) , 7.57 (2H, d), 7.73 (2H, d) , 8.06 (IH, d) , 10.20
(IH, s), 10.24 (IH, s), 12.02 (IH, br s) ; IR (solid)
3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371,
1338, 1316, 1253; 1161, 1137, 1062, 1038, 994, 958, 823;
30 MS 492.4 (M+H)*

Example 74 [2- (4-Acetamidophenylsulfanyl) -7-hydroacy-
guinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine

-252-

(Ila-74) : Prepared from IIa-40 according to Method H to
afford an off-white solid, mp 246-248 «C; NMR (DMSO) 6
2.00 {3H, S) , 2.08 (3H, s) , 5.52 (IH, s), 6.78 (IH, s) ,
6.87 (IH, d) , 7.54 (2H, d) , 7.72 {2H, d) , 8.37 (IH, d) ,
S 10.06 {IH, s), 10.17 (IH, S), 10.37 (H, s), 11.95 (IH, br
s) ; IR (solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420,
1389, 1359, 1298, 1223, 1176, 1148, 1087, 1026, 1010,
965; MS 407.4 (M+H)*

10 Example 75 [2- (4-Acetaiiiidophenylsulf anyl) -7- (3-

dimethylamino-propoxy) -quixiazolin-4-yll - ( 5 -methyl - 2H-
pyraaol-3-yl) -amine (IIa-75) : Prepared in a manner
similar to the above described Method I to afford an off-
white solid, mp 249-250 "C; NMR (DMSO) 5 1.90 (2H,

15 quint.), 2.01 (3H, s) , 2.09 (3H, s) , 2.19 (6H, s) , 2.42
(2H, m), 4.12 (2H, t) , 5.55 (IH, s) , 6.93 (IH, s) , 6.98
(IH, d) , 7.55 (2H, d) , 7.73 (2H, d) , 8.43 (IH, d) , 10.21
(IH, s) , 10.23 (IH, s), 11.98 (IH, br s) ; IR (solid)
3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420,

20 1394, 1344, 1320, 1292, 1263, 1222, 1168, 1048, 1034,
1005, 967, 864, 844; MS 492.4 (M+H)*

Example 76 (2-{4- [2- (tert-Butoxyceurbonyl-methyl-amino) -
acetylamino] -phenylsulfanyl>-quinazolin-4-yl) - (S-methyl-

25 2H-pyrazol-3-yl) -amine (IIa-76) : Prepared in a manner

similar to the above described Method E to afford a white
solid, mp 228-229«'C (dec); ^H NMR (DMSO) 5 1.37 (3H, s) ,
1.40 (3H, s) , 2.02 + 2.03 (3H, 2xs) , 2.88 + 2.90 {3H,
2xs), 4.01 +4.02 (2H, 2X3 ) , 5.52 + 5.57 (IH, 2xs) , 7.47

30 (IH, t), 7.55-7.63 (3H, m) , 7.75-7.80 (3H, m) , 8.60

(lH,d), 10.28 + 10.30 (IH, 2xs) , 10.45 (IH, s) , 12.08
(IH, S).; IR (solid) 1698, 1683, 1653, 1617, 1594, 1559,

-253-

1538, 1532, 1507, 1488, 1457, 1418, 1397, 1364, 1346,
1307, 1287, 1246, 1151, 842, 827, 759; MS 520.4 (M+H)*

Example 77 {2- [4- (2-lIethylaniino-acetylaininp) -
5 phenylsulf anyl] -qiiinazolin-4-yl} - (5-methyl-2H-pyrazol-3 -
yl) -amine {lIa-77) : Prepared in a manner similar to the
above described Method E to afford a white solid, mp 242-
2440C; NMR (DMSO) 5 2.01 (3H, s) , 2.34 (3H, s) , 3.32
(2H, S) , 5.58 (IH, S), 7.45 (IH, t) , 7.50-7.60 (3H, m) ,
10 7.75 (IH, t), 7.80 (2H, d) , 8.55 (IH, d) , 10.10 (IH, br
s) , 10.42 (IH, s) , 12.02 (IH, s) ; IR (solid) 1674, 1619,
1598, 1570, 1525, 1483, 1417, 1363, 1345, 1298, 1285,
1247, 1160, 966, 827, 804, 784, 763, 712, 670, 653; MS
420.4 (M+H)*

15

20

Example 78 [2- (4-Acetaiaidophenylsulf euiyl) -8-f luoro-
quinazolin-4-yll - (5-metliyr-2H-pyrazol-3-yl) -amine (Ila-
78) : Prepared in a manner similar to the above described
Method E to afford a white solid, mp 257-259«»C; ^H NMR
(DMSO) 5 2.01 (3H, S), 2.09 (3H, S> , 5.49 (IH, s) , 7.42
(IH, t) , 7.57-7.68 (3H, m), 7.75 (2H, d) , 8.40 (IH, d) ,
10.28 (IH, s), 10.75 (IH, s) ; "P NMR (DMSO) 6-1273; IR
(solid) 16&0, 1670, 1637, 1609, 1588, 1543, 1519, 1493,
1456, 1434, 1395, 1366, 1332, 1315, 1289, 1254, 1242,
25 1032, 83a, 829, 808, 744; MS 409.4(M+H)*

Example 79 ( IH-Indazol- 3 -yl )- (2 -phenylsulf anyl-
quinazolin-4-yl)-amine (IIa-79) : Prepared in a manner
similar to the above described Method E to afford a white
30 solid. ^'H NMR (DMSO) 5 7.07 (m, 3H) , 7.19 (t, IH) , 7.37

(d, 2K), 7.39 (t, IH), 7.52 (dd, IH), 7.54 (t, IH) , 7.55

-254-

(d, IH), 7.56 (t, m, 7.83 (t, IH) , 8.53 (d, IH) , 10.71
(S, 1H>, 12-85 (s, IH) ; MS 370.1 (M+H)*

Example 80 {2- [ (2-Hydro3cyethyl)phenylainino] -quinazolin-4-
yl}- (5-iBethyl-2H-pyrazol-3-yl) -amine (llc-1) : • Prepared in
a manner similar to the above described Method A to
afford a brown solid, mp 217«>C; NMR (DMSO) 8 1.99 {3H,
s), 3.69 (2H, t) , 4.05 (2H, t) , 5.00 (IH, br s) , 5.53
(IH, br S) , 7.09 (IH, m) , 7.25-7.40 (4H, m) , 7.40-7.48
(2H, m), 7.54 (IH, m) , 8.34 (IH, m) , 10.07 (IH, s) , 11.67
(IH, br s) ; IR (solid) 3395, 3155, 3052, 2934, 1623,
1598, 1577, 1475, 1434, 1393; MS 361.2 (M+H)*

Example 81 [2- (Methylphenylamino) -quinazolin-4-yl] - (5-
niethyl-2H-pyrazol-3-yl) -amine (lIc-2) : Prepared in a
manner similar to the above described Method A to afford
a white solid, mp 154-156"'C; ^H NMR (DMSO) 5 2.03 (3H, s) ,
3.51(3H, s) , 5.70(1H, s) , 7.13(1H, m) , 7 . 36-7 . 25 (3H, m) ,
7.48-7.37 (3H, m) , 7.58 (IH, m) , 8.38 (IH, d) , 9.98(1H,
S) , 11.91 (IH s); IR (solid) 1621, 1598, 1578, 1540,
1494, 1473, 13&8, 1374; MS 331.0 (M+H)*

Example 82 (5-methyl-2H-pyrazol-3-yl) -{2- [N-methyl-N-
(pyridin-3-ylmethyl) amino] -quinazolin-4-yl}-amine
(XIc-3) : Prepared in a manner similar to the above
described Method A to afford a yellow solid, 177«»C; ^H
NMR(IM4SO), S 0.45 (2H, s) , 0.84 (2H, s) , 1.80 (IH, s) ,
3.16 (3H, s) , 4.93 (2H, s) , 6.18 (IH, br s) , 7.10 (IH,
t)., 7.34 (2H, S), 7.55 (IH, t) , 7.64 (IH, s) , 8.36 (IH,
d) , 8.45 (IK, S), 8.52 (IH, s) , 10.03 (IH, s) , 12.17 (OH,
s); IR (solid) 3104, 2995, 2936, 1618, 1591, 1559, 1541,
1518, 1477, 1409, 1386, 1350, 1300, 1018, 991, 873, 827;
MS 372.3 (M+H)*

10

-255-

Example 83 (5-Methyl-2fl'-pyrazol-3-yl) - (2-phenylaniino-
quinazolin-4-yl) -amine (ZZc-4) : Prepared in a manner
similar to the above described Method A to afford a white
solid; NMR (DMSO ®60**C> 8 2;27(3H, s) , 6.47<1H, br s) ,
6.92(1H, m) , 7.31 (3H, m) , 7.53 (IH, m) , 7.70 (IH, m) , 7.91
(2H, m> , 8.37 (2H, d) , 9.16 (IH, br s) , 10.05 (IH, br s) ,
12.15 (IH, br s) ; IR (solid) 1623, 1601, 1573, 1541,
1478 ,- MS 317 . 0 (M+H) *

Example 84 (2-Benzylamino-quinazolin-4-yl) - ( 5 -methyl - 2H-
pyrazol-3-yl) -amine (IIc-5) : Prepared in a manner similar
to the above described Method A to afford a white solid,
mp 225-227«'C; *H NMR (DMSO) 8 2.20 (3H, s) , 4.62(2H, d) ,
15 7.18 (IH, s) , 7.43-7.6(>(8H, m) , 8.22 (IH, s) , 9.99 (IH,
br s) , 12. 05 (IH, br s) ; IR (solid) 1630, 1609, 1578,
1538, 1511; MS 331.0 (M+H)*

Example 85 (2-Cyclohe3cylamino-cpiinazolin-4-yl) - (5-methyl-
20 2H-pyrazol-3-yl) -amine (IIc-6) ; Prepared in a manner

similar to the above described Method A to afford eui off-
white solid, mp 280«»C (dec); ^H NMR (DMSO) 5 1.11-
1.44(5H, m) , 1.56 (IH, m) , 1.71(2H, m) , 1.92 (2H, m) ,
2.26 (3H, s) , 3.75(1H, s) , 6.63 (IH, br s) , 7.04 (IH, s) ,
25 7.28 (IH, s) , 7.51(1H, m) , 8.26(1H, s) , 9.97(1H, br s) ,
12.08(1H, br s), 12.75(1H, br s) ; IR (solid) 2927, 2853,
1619, 1596, 1569, 1522, 1482; MS 323.0 (M+H)*

Example 86 [2- (2,3-Dihydrobenzo[l,4]dioxin-6-ylamino) -
30 quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine
(IIc-7) : Prepared in a manner similar to the above
described Method A to afford an off -green solid, mp

O

-256-

>250*»C; NMR (DMSO) 8 2.23 (3H, s) , 4.15 (4H, m), 6.32
(IH, br s>, 6.76 (IH, d), 7.16 (IH, t) , 7.22 (IH, dd) ,
7.39 (IK, d), 7.57 (IH, t) , 7.66 (IH, s) , 8.34 (IH, d) ,
9.07 (IH, br s), 10.20 (IH, br s) , 12.15 (IH, br s) ; IR
5 (solid) 3445, 3045, 2968, 2927, 2868, 1618, 1595, 1577,
1559, 150&, 1441, 1377, 1073; MS 375.1 (M+H)*

Example 87 (2-Cyclohexylmeth.ylaia±no-quinazoliii-4-yl) - (5-
inethyl-2H-pyrazol-3-yl)-ainlne (IIc-8) : Prepared in a

10 manner similar to the above described Method A to afford
a white solid, mp 211°C; NMR (DMSO) 5 0.85-1.30 (5H,
m), 1.50-1.85 (6H, m) , 2.22 (3H, s) , 3.19 (2H, s) , 6.50-
7.00 (IH, br s) , 7.06 (IH, br s) , 7.29 (IH, br s) , 7.51
(IH, t>, 8.26 (IH, br s), 9.97 (IH, br s), 12.04 (IH, br

15 s) , 12.75 (IH, br S) ; IR (solid) 3333, 2927, 2850, 2831,
1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 988; MS
337.4 (M+H)*

Example 88 [2- {U-Indazol-6-ylamino) -quinazolin-4-yl3 - (5-
20 methyl-2H-pyrazol-3-yl) -amine (Ilc-9) : Prepared in a

manner similar to the above described Method A to afford
an. off -white solid, rap >250°C; ^H NMR (DMSO) 6 2.24 (3H,
S) , 5.93 and 6.89 (IH, 2xbr s) , 7.05-8.15 (6H, m) , 8.25-
8.90 (2H, m), 9.25 and 9.97 (IH, 2xbr s) , 10.11 and 10.57
25 (IH, 2xbr s) , 12.15 and 12.80 (2H, 2xbr s) ; IR (solid)

3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1
(M+H)*

Example 89 ( 5 -Me thyl - 2H-pyrazol - 3 -yl) - [2 - (pyridin- 3 -
30 ylmethylamino) -qalnazolin-4-yl] -amine (IIc-10) : Prepared
in a manner similar to the above described Method A to
afford an off-white solid, mp 218«C; ^H NMR (DMSO) 5 2.20

-257-

OH, S), 4.5& (2H, a), 6.30 (IH, br S) , 7.10 {IH, s) ,
7.33 (2K, S), 7.54 (IH, s) , 7.78 (IH, s) , 8.31 (IH, s) ,
8.43 (IH/ S) , 8.61 (IH, S> , lO.O (IH, br s) , 12.15 (IH,
br s) ; IR (solid) 3308, 2945, 2919, 2858, 1623, 1593,
5 1577, 1552, 1501, 1475, 1449, 1383; MS 332.1- (M+H)*

Example 90 [2- (3-C!hlorophenylamino) -quinazolin-4-yl] - (5-
methyl-2B-pyrazol-3-yl) -amine (IZc-11) : Prepared in a
manner similar to the above described Method A to afford
10 an off-white solid, mp >250°C, NMR (DMSO) 5 2.29 (3H,

s) , 5.30-6.98 (IH, m) , 6.96 (IH, s) , 7.28 (2H, s) , 7.51 ©
(IH, s) , 7,67 (IH, s) , 7.77 (IH, s) , 8.23 (IH, s) , 8.46
(IH, s) , 9.35 and 10.00 (IH, 2xbr s) , 10.14 and 10.64
(IH, 2xbr s) , 12.20 and 12.82 (IH, 2xbr s) ; IR (solid)
15 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549,
1472, 1440, 1403, 1372; MS 351.1 (M+H) *

Example 91 t2- (4-Chlorophenylaiiiino) -quinazolin-4-yl] - (5-
inethyl-2H-pyrazol-3-yl) -amine. {IIc-12) : Prepared in a

20 manner similar to tbe above described Method A to afford
an off-white solid, mp >250<»C; ^H NMR (DMSO) 8 2.27 (3H,
s) , 5.20-6.80 (IH, m) , 7.26 (IH, s) , 7.33 (2H, s) , 7.51 O
(IH, S) , 7.66 (IH, s) , 7.99 (2H, d) , 8.42 (IH, s) , 9-29
and 9.93 (IH, 23cbr s) , 10.13 and 10.55 (IH, 23cbr s) ,

25 12.19 and 12.81 (IH, 2xbr s) ; IR (solid) 3439, 3057,
2957, 1618, 1600, 1586, 1572, 1550, 1504, 1486, 1431,
1413, 1367; MS 351.1 (M+H)*

Example 92 [2- (4-Fluorobenzylamino) -quinazolin-4-yl] - (5-
30 methyl-2H-pyrazol-3-yl) -amine (IIc-13) : Prepared in a

manner similar to the above described Method A to afford
a white solid, mp 216'»C; ^H NMR (DMSO) 6 2.20 (3H, s) ,

-25&-

4.56 (2H, d), 6.30 (IH, br s) , 7.05-7.20 (3H, m) , 7.31
(IH, d), 7.42 (2H, s), 7.54 (IH, t) , 8.32 (IH, s) , 10.01
and 10.34 (IH, 23cbr b) , 12.09^ and 12.75 (IH, 2xbr s) ; IR
(solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367;
5 MS 349.3 (M+H)*

Example 93 {2- [2- (2-Hydro3cyethyl)plienylaniino] -quinazolin-
4.yl}. (5-iBethyl-2H-pyrazol-3-yl) -amine (lIe-14) : Prepared
in a manner similar to the above described Method A to

10 afford a white solid, mp 222«'C; ^H NMR (DMSO) 8 2.09 {3H,
O s), 2,80 (2H, t) , 3.61 (2H, t) , 4.87 (IH, br s) , 5.85

(IB, br s), 7.30-7.53 (5H, m) , 7.63 (IH, d) , 7.86 (IH,
t) , 8.68 (IH, d) , 10.11 (IH, br. s) , 11.55 (IH, br s) ,
12.49 (IH, br s) , 13.50 (IH, br s) ; IR (solid) 3193,

15 3171, 3111, 3084, 1636, 1577, 1559, 1509, 1486, 1413,
1340, 1058; MS 361.3 (M+H)*

Example 94 [2- (4^Cyanomethylphenylamino) -<iuinazolin-4-
yl] - (5-metJiyl-2H-pyrazol-3-yl) -amine (lIc-15) : Prepared

20 in a manner similar to the above described Method A to
afford an off-white solid, mp >250°C; ^H NMR (DMSO) 2.23
( ) (3H, s) , 4.09 (2H, S) , 6.28 (IH, br s) , 7.41 (2H, d) ,

7.48 (IH, t), 7.57-7.63 (3H, m) , 7.87 (IH, t) , 10.70 (IH,
s), 11.56 (IH, s), 12.63 (IH, br s) , 13.25 (IH, br s) ; IR .

25 (solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513,
1481, 1413, 1336, 1158, 999; MS 356.2 (M+H)*

Example 95 [2 - (3 -Hydroxymethylphenylamino) -quinazolin-4-
yl] -(5-methyl-2ff-pyrazol-3-yl) -amine (IIc-16) : Prepared
30 in a manner similar to the above described Method A to

afford an off-white solid, mp >250»C; ^H NMR (DMSO) 6 2.20
(3H, s) , 4.53 (2H, s) , 5.22 (IH, br s) , 6.31 (IH, br s) ,
7.24 (IH, d) , 7.33-7.53 (4H, m) , 7.61 (IH, d> , 7.86 (IH,

-259-

t) , 8.67 (IH, d) , 10.61 (IH, br s) , 11.52 (IH, br s) ,

12.59 (IH, br s) , 13.10 (IH, br s) ; IR (solid) 3401,

3209, 3108, 3071, 2975, 2916, 1632, 1609, 1595, 1554,

1485, 1421, 1371, 1348, 1046, 1005, 813; MS 347.3 (M+H) *

5 ■ • •

Example 96 [2- (S-Hydroxyphenylamino) -quinazoliii-4-yl] - (5-
methyl-2H-pyrazol-3-yl) -amine (IIc-17) : Prepared in a
maimer similar to the above described Method A to afford
a white solid, mp >250*»C; NMR (DMSO) 5 2.22 (3H, s) ,

la 6.42 (IH, br s) , 6.72 (IH, d) , 6.97 (2H, s) , 7.21 (IH,
t>, 7.47. (IH, t) , 7.60 (IH, d) , 7.85 (IH, t) , 8.67 (IH,
d) , 9.76 (IH, s) , 10.53 (IH, s) , 11.53 (IH, s) , 12.58
(IH, br s) , 12.99 (IH, br s) ; IR (solid) 3354, 3027,
2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332,

15 1154, 1004; MS 333.2 (M+H)*

Example 97 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-
phenylaiBino-quinazolia-4-yl) -amine (lIc-18) : Prepared in
a maimer similar to the above described Method A to _

20 afford an off-white solid, mp 234'»C; NMR (DMSO) 5 0.74
(2H, s), 6.92 (2H, s), 1.91 (IH, s) , 5.83 and 6.54 (IH,
2xbr s) , 6.94 (IH, t) , 7.30 (3H, m) , 7.50 (IH, s) , 7.65
(IH, S) , 7.91 (2H, d), 8.27 (IH, s) , 9.13 and 9.77 (IH,
2xbr s) , 10.07 and 10.52 (IH, 2xbr s) , 12.19 and 12.82

25 (IH, 2xbr s) ; IR (solid) 3443, 1622, 1595, 1577, 1554,

1486, 1449, 1413, 1376, 1340, 1235, 1171, 988, 806; MS
343.2 (M+H)*

Example 98 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-
30 methylphenylamino) -quinazolin-4-yl] -amine (IIc-19) :

Prepared in a manner similar to the above described
Method A to afford an off-white solid, ti^ 117»C; ^H NMR
(DMSO) 6 0.72 (2H, s) , 0.92 (2H, s) , 1.90 (IH, m) , 2-32

-260-

(3H, s) , 6.20 (IH, Tor 8), 6.80 (IH, d) , 7.20 (IH, t) ,
7.27 (IH, brs), 7.51 (IH, br s) , 7.55-7.85 (3H, m) , 8.43
(IH, br s) , 9.50 (IH, br s) , 10.44 (IH, s) , 12.55 (IH, br
S) ; IR (solid) 3303, 1618, 1581, 1554, 1536, 1495, 1472,
5 1436, 1413., 1372, 1336, 1240, 990; MS 357.4 (M+H)*

Exantple 99 ( 5 - Cyclopropyl - 2H-pyrazol - 3-yl)-[2-(6-
inethoxypyridin-3-ylaiBino) -cpiiiiazolln-4-yl] -eoolne
(IIc-20) : P,repared in a manner similar to the above

10 described Method A to afford a pink solid, rap 120 ••C; ^H
NMR (DMSO) 5 0.72 (2H, s) , 0.91 (2H, s) , 1.89 (IH, m) ,
3.85 (3H, s), 6-20 (IH, br s) , 6.82 (IH, d) , 7.25 (IH,
S) , 7.48 (IH, m), 7.66 (IH, t) , 8.13 (IH, br s) , 8.42
(IH, br s) , 8.61 (IH, br s) , 9.50 (IH, br s) , 10.48 (IH,

15 br s>, 12.55 (IH, br s) ; IR (solid) 3457, 3439, 1622,
1604, 1577, 1554, 1481, 1422, i386, 1363, 1272, 1235,
1035, 985, 821; MS 374.2 (M+H)*

Example 100 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (indan-5-
20 ylamino)-quinazolin-4-yl] -amine (Ilc-21) : Prepared in a
manner similar to the above described Method A to afford
a pale bfown solid, mp 199-204''C; ^H NMR (DMSO) 5 0.69
(2H, br s) , 0.91 (2H, br s) , 1.90 (IH, m) , 2.02 (2H, m) ,
2.68 (IH, m), 2.83 (3H, m) , 6.46 (IH, brs), 7.18 (IH,
25 d) , 7.26 (IH, br s) , 7.50 (IH, d) , 7.67 (IH, t) , 7.75

(IH, br s) , 8.45 (IH, br s) , 9.70 (IH, br s) , 10.60 (IH,
br s) , 12.30 and 12.80 (IH, 2xbr s) ; IR (solid) 1621,
1601, 1572, 1552, 1495, 1474, 1439, 1425, 1408, 1382,
1363, 1319, 1267; MS 383.3 (M+H)*

30

Example 101 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (LH-indol-
6-ylamino) -qulnazolin-4-yl] -amdLne (Ilc-22) : Prepared in a
manner similar to the above described Method A to afford

-261-

a dark brown solid, vap >300<»C; NMR {DMSO) 8 0.69 (2H,
br s) , 0.89 (2H, br s) , 1.88 (IH, m) , 5.77 and 6.74 (IH,
2xbr s) , 6.35 (IH, s) , 7.22 (3H, br s) , 7.45 (2H, d) ,
7.65 (IH, s) , 8.35 (2H, br s) , 8.86, 9.70 and 10.01 (IH,
5 3xbr s) , 10.49, 12.12 land 12.84 (IH, 3xbr s), 10.94 (s,
IH) ; IR (solid) 1623, 1603, 1571, 1549, 1495, 1477, 1460,
1419, 1383, 1336, 1264, 1250, 1238; MS 382.4 (M+H)*

Exanvple 102 [2- (4-Acetainido-3-methylphenylamino) -
10 quinazolin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) -amine
(IIc-23) : Prepared in a mamner similar to the above
described Method A to afford an off-white solid, mp
>188''C (dec); NMR (DMSO) 5 0.72 (2H, br s) , 0.94 (2H,
br s), 1.92 (IH, m), 2.03 (3H, s) , 2.19 (3H, s) , 5.80 and
15 6.69 (IH, 2xbr s) , 7.22 (2H, br s) , 7.49 (IH, br s) , 7.70
(3H, m) , 8.35 (IH, br s) , 9.01, 9.59 and 10.01 (IH, 3xbT
s) , 9.19 (IH, s) , 10.53, 12.16 and 12.81 (IH, 33d>r s) ; IR
(solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428, 1403,
1343, 1320, 1307, 1250; MS 414.4 (M+H) *

20

Example 103 [2- {4-C2iloro-3-inethylphenylamino> -quinazolin-
4-yll - (5-cyclqpropyl-2,ff-pyrazol-3-yl) -amine (Ilc-24) :
Prepared in a manner similar to the above described
Method A to afford a pale brown solid, mp 244-246«>C; ^H

25 NMR (DMSO) 5 0.69 (2H, br s) , 0.94 {2H, br s) , 1.91 (IH,
m), 2.32 (3H, s) , 5.89 and 6.63 (IH, 2xbr s) , 7.28 (2H,
m), 7.49 (IH, m), 7.65 (IH, m) , 7.80 (IH, br s) , 7.86
(IH, s) , 8.40 (IH, br s) , 9.17, 9.81 and 10.06 (IH, 3xbr
s) , 10.58, 12.19 and 12.78 (IH, 3xbr s) ; IR (solid) 1615,

30 1S78, 1549, 1475, 1419, 1397, 1365, 1331, 1296, 1261,
1238, 1187, 1139; MS 391.4 (M+H) *

-262-

Example 104 ( 5 -Cyclopropyl - 2H-pyrazol - 3 -yl) - [2 - (4 -
ethylphenylamino) -^inazolin-4-yl] -amine (lIc-25) :
Prepared in a manner similar to the above described
Method A to afford a pale brown solid, mp 250-251«'C;
5 NMR (DMSO) 6 0.72 (2H,- br s) , 0.91 (2H, br s) , 1.19 (3H,
t), 1.91 (IH, m) , 2.58 (2H, q) , 5.81 and 6.64 (IH, 2xbr
s) , 7.15 (2H, d)/ 7.22 (IH, s) , 7.47 (IH, s) , 7.64 (IH,
S) , 7.78 (2H, S) , 8.36 (IH, br s) , 9.03, 9.66 and 10.05
(IH, 3xbr s) , 10.49, 12.20 and 12.80 (IH, 3xbr s) ; IR
10 (solid) 1603, 1574, 1546, 1509, 1497, 1474, 1439, 1417,.
1386; MS 371.5 (M+H) *

Example 105 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (4-
propylphenyl amino) -quinazolin-4-yl] -amine (IIc-26) :

15 Prepared in a manner similar to the above described
Method A to afford an off-white solid, mp 255-2560C;
NMR (DMSO) 5 0.72 (2H, br s) , 0.91 (5H, t) , 1.60 (2H, m) ,
1.90 (IH, m), 2.58 (2H, q) , 5.81 and 6.63 (IH, 2xbr s) ,
7.12 {2H, d), 7.21 (IH, s) , 7.47 (IH, s) , 7.63 (IH, s) ,

20 7.77 (2H, s) , 8.36 (IH, br s) > 9.01, 9.70 and 10.11 (IH,
3x br s) , 10.51, 12.17 and 12.80 (IH, 3xbr s) ; IR (solid)
1595, 1571, 1545, 1499, 1477, 1442, 1413, 1388; MS 385.6
(M+H)-^

25 Example 106 (5-Cyclopropyl-2H-pyrazol-3-yl) -{2- [4- (2-
hydroxyethyl ) phenylamino] -quinazolin-4 -yl} -amine
(llc-27) : Prepared in a manner similar to the above
described Method A to afford a pale brown solid, mp 255-
256»C; ^H NMR (DMSO) 5 0.73 (2H, br s) , 0.91 (5H, t) , 1.90

30 (IH, m), 2.69 {2H, t) , 3.60 (2H, q) , 4.62 (IH, t) , 5.81
and 6.65 (IH, 2xbr s) , 7.15 (2H, d) , 7.22 (IH, s) , 7.46
(IH, s) , 7.63 (IH, s), 7.77 (2H, s) , 8.36 (IH, br s) ,

-263-

9.05, 9.69 and 10.02 (IH, 3xbr s) , 10.52, 12.17 and 12.79
(IH, 3xbr s) ; IR (solid) 1632, 1569, 1546, 1483, 1452,
1434, 1402, 1371, 1267, 1231; MS 387.4 (M+H)*

5 Example 107 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-

phenetylamln6-quinazolin-4-yl) -amine (IIc-28) : Prepared
in a manner similar to the above described Method A to
afford a white solid, mp >250«»C; NMR (DMSO) 5 0.66 (2H,
m) , 0.84 (2H, m) , 1.83 <1H, m) , 2.90 (2H, t) , 3.56 (2K-,
10 ra) , 6.29 (IH, br s) , 7.01 (IH, t) , 7.12-7.38 (6H, m) ,

7.48 (IH, t), 8.42 (IH, s) , 10.91 (IH, br s) , 13.11 (IH,
br s) ; IR (solid) 2922, 1650, 1627, 1577, 1550, 1500,
1482, 1395, 1368, 1004, 832; MS 371.3 (M+H)*

15 Example 108 [2- (2-Cycloliexylethylamino) -quinazolin-4-yl] -
(5-cyclopropyl-2H-pyrazol-3-yl) -amine {Ilc-29) : Prepared
in a meuiner similar to the above described Method A to
afford a white solid, mp >250°C; ^H NMR (DMSO) 8 0.70 (2H,
s) , 0.80-1.00 (4H, m) , 1.05-1.30 (4H, m) , 1.30-1.50 (3H,

20 m) , 1.55-1.80 (5H, m), 1.87 (IH, s) , 5.40-6.70 (2H, br
S) , 7.04 (IH, S) , 7.25 (IH, s) , 7.49 (IH, s) , 8.25 (IH,
s) , 10.06 (IH, br s) ^ 11.93 (IH, br s) ; IR (solid) 3448,
2920, 2852, 1618, 1600, 1568, 1550, 1486, 1418, 1395,
1367, 1258, 1008, 985; MS 377.4 (M+H)*

25

Example 109 t2- (4-Carboacymethoacyphenylamino) -quinazolin-
4-yll - (5-cyclopropyl-2H-pyrazol-3-yl) -amine (Ilc-30) :
Prepared in a manner similar to the above described
Method A to afford a yellow solid, mp >250«»C; MMR
30 (DMSO) 0.72 (2H, m) , 0.91 (2H, m) , 1.90 (IH, m) , 4.62

(2H, S) , 6.24 (IH, s) , 6.88 (2H, s) , 7.21 (IH, m) , 7.45
(IH, m) , 7.62 (IH, m) , 7.78 (2H, m) , 8.35 (IH, m) , 9.31
(IH, s) , ip.25 (IH, s), 11.70 (IH, br s) ; IR (solid)

-264-

1663, 1595, 1563, 1509, 1422, 1331, 1240, 1176, 1053,
999 ; MS 417-3 (M+H) *

Example 110 [2- (4-Cyanc»netfa,ylphenylsuBino) -qainazolin-4-
5 yl] - (5-cyclopropyl-2H-pyrazol-3-ylf -amine • (IIc-31) :
Prepared in a manner similar to the ahcfv& described
Method A to afford a white solid, mp 222«»C; NMR (DMSO)
6 0.74 (2H, m) , 0.93 (2H, m) , 1.92 (IH, m) , 3.97 {2H, s) ,
5.82 and 6.65 (IH, 2xbr s> , 7.29 (3H, m) , 7.50 (IH, ra) ,
10 7.66 (IH, m) , 7.92 (2H, m) , 8.39 <1H, m) , 9.21 and 9.85
(IH, 2xbr s) , 9.90 and 10.56 (IH, 2xs), 12.19 and 12.80
(IH, 2xbr s) ; IR (solid) 1641, 1622, 1595, 1581, 1554,
1513, 1486, 1463, 1408, 1372, 985, 821; MS 382.3 (M+H)*

15 Example ill [2- (Benzothiazol-6-ylamino) -quinazolin-4-yl] -
(5-cyclopropyl-2Jff-pyrazol-3-yl) -amine (IIc-32) : Prepared
in a manner similar to the above described Method A to
afford an off-white solid, mp 255-256«>C; ^H NMR (DMSO) 5
0.73 (2H, m) , 0.92 (2H, m) , 1.92 (IH, m) , 5.83 and 6.63

20 (IH, 2xbr s) , 7.27 (IH, br s) , 7.59 (IH, br s) , 7.68 (IH,
br s), 7.79 (IH, br s) , 7.98 (IH, br s) , 8.41 (IH, br s) ,
8.97 (IH, br s), 9.19 (IH, s) , 9.58 and 10.10 (IH, 23Cbr
s) , 10.57, 12.21 and 12.85 (IH, 33d5r s) ; IR (solid) 1624,
1592, 1575, 1512, 1472, 1411, 1377, 1333, 1244; MS 400.3

25 (M+H)*

Example 112 (5-Cyclopropyl-2JSr-pyrazoi-3-yl) - [2- (3,4-
dimetbylphenylamino) -quinazolin-4-yl] -amine (IIc-33) ;
Prepared in a manner similar to the above described
30 Method A to afford a white solid, mp 245-246«»C; ^H NMR

(DMSO) 5 0.72 (2H, br s) , 0.90 (2H, br s) , 1.90 (IH, m) ,
2.18 (3H, s) , 2.23 (3H, s) , 5.77 and 6.63 (IH, 2xbr s) ,

-265-

7.09 (IH, d), 7.23 (IH, br s) , 7.47 (IH, br s) , 7.59 (IH,
br s) , 7.64 (IH, br s) , 8.36 (IH, br s) , 9.02, 9.55 and
10.07 (IH, 3xbr s) , 10.49, 12.31 and 12.80 (IH, 3xbr s) ;
IR (solid) 1620, 1600, 1574, 1552, 1497, 1474, 1436,
1416, 1385, 1262; MS 371.5 (M+H) *

Example 113 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2-
phenoxyethylamino) -quinazolin-4-yl] -amine (Ilc-34) i

Prepared in a manner similar to the above described —
Method A to afford a white solid, mp 203 °C; NMR (DMSO)
5 0.70 (2H, m), 0.88 (2H, m) , 1.87 (IH, m) , 3.73 (2H, d) ,
4.16 (2H, s) , 5.75 and 6.70 (IH, 2xbr s) , 6.93 (IH, t) ,
6.90-7.20 (3H, m) , 7.20-7.45 (3H, m) , 7.55 (IH, s) , 7.76
(IH, br s) , 8.32 (IH, s) , 9.95 and 10.35 (IH, 2xs) , 12.13
and 12.75 (IH, 2xbr s) ; IR (solid) 3434, 1622, 1600,
1572, 1554, 1499, 1476, 1422, 1399, 1385, 1303, 1267,
1226, 1212, 1052, '829; MS 387.4 (M+H) *

Example 114 (S-Cyclopropyl-2H-pyrazol-3-yl) - [2- (thiophen-
2-niethylamino) -quxnazolin-4-yl] -aauine (Ilc-35) : Prepared
in a manner similar to the above described Method A to
afford a white solid, rap 2120C? ^H NMR (DMSO) 6 0.67 (2H,
m), 0.90 (2H, m), 1.86 (IH, m) , 4.74 (2H, d) , 5.76 and
6.66 (IH, 2xbrs), 6.95 (IH, s) , 6.90-7.20 (2H, m) ,
7.20-8.45 (5H, m) , 9.94 and 10.40 (IH, 2xs) , 12.13 and
12.71 (IH, 2xbr s) ; IR (solid) 3444, 2948, 2847, 1622,
1600, 1559, 1500, 1481, 1418, 1390, 1358, 1336, 1313,
1263, 1217, 1185, 1149, 990, 821; MS 363.4 (M+H)*

Example 115 [2- (4-Csucboxymethylphenylajaino) -quinazolin-4-
yl] - (5-cyclopropyl-2H-pyrazol-3-yl) -amine (ZIc-36) :

Prepared in a manner similar to the above described
Method A to afford a brown solid, mp >210«C (dec); ^H NMR

V -266-

(DMSO) 6 0.64 {2H, br s>, 0.92 (2H, m) , 1.92 (IK, m) ,
3.50 (2H, S) , 5.76 and 6.54 (IH, 2xs) , 7.19 (IH, s) , 7.24
(IH, tn) , 7.49 (IH, d) , 7.64 (IH, t) , 7.84 (2H, d) , 8.37
(1H> m) , 10.27 and 12.25 (IH, 2xbr s) ; IR (solid) 1648,
5 1591, 1555, 1512, 1489, 1428, -1411; 1374; MS 401.4 (M+H)*

Example 116 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (IH-
indazol-5-ylamino) -cniinazolixi-4-yl] -amine (lIc-37) :

Prepared in a manner similar to the above described
10 Method A to afford a purple solid, mp 268-271"»C; NMR
J (DMSO) 5 0.69 (2H, br s) , 0.90 (2H, m) , 1.88 (IH. m) ,

5.86 and 6.58 (IH, 2xs) , 7.22 (IH, s) , 7.61 (IH, s) , 7.71
(2H, m) , 8.01 (IH, s) , 8.37 (2H, s) , 8.58, 9.05 and 9.58
(IH, 3xbr s) , 10.01, 10.68 and 12.38 (IH, 3xbr s) , 12.90
15 (IH, s) ; IR (solid) 1626, 1605, 1576, 1546, 1512, 1495,

1476, 1447, 1431, 1416, 1393, 1261, 1224; MS 3 83.3 (M+H)*

Example 117 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (pyridin-r
3-ylmethylamino) -quinazolin-4-yl] -amine (lIc-38) :

20 Prepared in a manner similar to the above described

Method A to afford a yellow solid, mp 193 «C; ^H NMR (DMSO)
5 0.69 (2H, m), 0.89 (2H, m) , 1.86 (IH, m), .4.60 (2H, s) ,
5.76, 6.22 and 6.66 (IH, 3xbr s) > 7.10 (IH, s) , 7.33
(2H, s), 7.54 (IH, s), 7.78 (IH, s) , 8.31 (IH, s) , 8.44

25 (IH, s) , 8.61 (IH, s) , 10.00 and 10.32 (IH, 2xs) , 12.15
and 12.63 (IH, 2xbr s) ; IR (solid) 2927, 2850, 1623,
1600, 1577, 1536, 1477, 1418, 1332, 1254, 814; MS 358.3
(M+H) *

30 Example 118 (5-Cyclopropyl-2flr-pyrazol-3-yl) - [2- (3-
methoxycarbonylphenylamino) -quinazolin-4-yl] -amine
(IIc-39) : Prepared in a manner similar to the above

-267-

described Method A to afford a white solid, mp 228-2310C;

NMR (DMSO) 8 0.73 (2H, br s) , 0.91 (2H, m) , 1.92 (IH,
m) , 3.88 (3H, s) , 5.99 and 6.79 (IH, 2xs) , 7.27 (IH, s) ,
7.46 {3H, m) , 7.68 (IH, s) , 8.36 (IH, d) , 8.48 (2H, s) ,
5 9.36, 9.84 and 10 . 00 (IH, 3xbr S), 10.63, 12.17 and 12 . 79
(IH, 3xbr s) ; IR (solid) 1716, 1615, 1591, 1579, 1557,
1473, 1432, 1416, 1379, 1334, 1298, 1276, 1226, 1191,
1142, 1110, 1020, 985; MS 401.3 (M+H) *

10 Bxampie 119 [2- (3-Carboxyphenylajnino) -quinazolin-4-yl] -
(5-cyclopropyl-2Br-pyrazol-3-yl) -aiaine (IIc-40) : Prepared
in a manner similar to the above described Method A to.
afford an- off-white solid, rap 298-302»C; ^H NMR (DMSO) 8
0.73 (2H, br s) , 0. 91 {2H, m) , 1.90 (IH,. m) , 7.26 (IH,

15 s) , 7.35 (IH, t), 7.50 (2H, d) , 7.66 (IH, t) , 8.31 (2H,
m) , 8.41 (IH, d>; IR (solid) 1661, 1597, 1578, 1558,
1517, 1486, 1424, 1385; MS 387.3 (M+H)*

Example 120 (5-Cyclpprc^pyl-2flr-pyrazol-3-yl) -. [2- (3-
20 ethylphenylamino) -guinazolin-4-yl] -amine (IZc-41) :
Prepared in a maimer similar to the above described
Method A to afford an off-white solid, mp 186-188'»C; ^H
NMR (DMSO) 8 0.73 (2H, br s) , .0.91 (2H, br s) , 1.22 (3H,
t) , 1.90 (IH, m) , 2.62 (2H, d) , 5.81 and 6.70 (IH, 2 X br
25 s) , 6.78 (lH,d), 7.20 (2H, s), 7.48 (IH, s) , 7.65 (IH,
s) , 7.69 (IH, s) , 7.81 (IH, s) , 8.38 (IH, br s) , 9.03,
9.74 and 10.03 (IH, 3 x br s) , 10.55, 12.16 and 12.82
(IH, 3 X br s) ; IR (solid) 1614, 1580, 1549, 1534, 1493,
1471, 1433, 1409, 1374, 1340, .1240, 1182, 1165, 1138; MS
30 371.3 (M+H)*

-268-

Bxample 121 {5-Cyclc^ropyl-2H-pyrazol-3-yl) - [2- (2,3-
dimethylphenylamino) -quiiiazolin-4-yl] -amine (IIc-42) :
Prepared in a maimer similar to the above described
Method A to afford an off-white solid, mp 241-242«»C;
NMR (DMSO) 5 0.58 (2H, br s), "0.86 (2H, d) , 1.77 (IH, br
s), 2.11 (3H, br s), 2.28 (3H, s) , 5.77 and 6.14 (IH, 2 x
br s,), 7.01 (IH, s), 7.11 (IH, t), 7.22 (IH, br s) , 7.29
(IH, d) , 7.56 (IH, s) , 8.36 (IH, br s) , 8.49, 8.98 and
9.98 (IH, 3 X br s) , 10.48, 12.04 and 12.68 (IH, 3 x br
S) ; IR (solid) 1622, 1603, 1573, 1552, 1495, 1471, 1440,
1428, 1412, 1384, 1268; MS 371.4 (M+H)*

Example 122 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3, 4-
dimethoxyphenylamino) -quinazolin-4-yll -amine (IIc-43) :
Prepared in a manner similar to the above described
Method A to afford a grey solid, mp 144°C; ^H NMR (DMSO) 5
0.69 (2H, S), 0.86 (2H, d) , 1.89 (IH, m) , 3.61 (3H, s),
3.67 (3H, s) , 5.76: (ih, br s) , 6.12 (IH, d) , 6.31 (IH,
S), 6.66 (IH, d), 6.94 (IH, d) , 7.27 (IH, t) , 7.50 (IH,
d) , 7.68 (IH, t) , 8.45 and 9.36 (IH, br s, rotamers) ,
9.42 and 10.54 (IH, s, rotamers), 12.29 and 12.82 (IH, br
s, rotamers); IR (solid) 3331, 3000, 2959, 2931, 2836,
1627, 1604, 1577, 1536, 1509, 1463, 1441, 1418, 1336,
1259, 1232, 1200, 1027; MS 403.8 (M+H)*

Example 123 (5-Cyclopropyl-2H-pyrazol-3-yl) - 12- (3-
methoxyphenylamino)-quinazolin-4-yl] -amine (IZc-44) :
Prepared in a manner similar to the above described
Method A to afford a grey solid, mp 207-2ll»C; *H MMR
(DMSO) 5 0.73 (2H, br s) , 0.91 (2H, br s) , 1.91 (IH, m) ,
3.77 (3H, s) , 5.81 and 6.71 (IH, 2 X br s) , 6.53 (IH, d) ,
7.19 - 7.85 (7H, m) , 8.34 (IH, s) , 9.08, 9.79 and 10.06

10

-269-

(IH, 3 X br s), 10.56, 12.16 and 12.82 (IH, 3 x br s) ; IR
(solid) 1611, 1580, 1549, 1533, 1498, 1477, 1430, 1409,
1374, 1337, 1253, 1204, 1180, 1157, 1141, 1041, 1030,
992; MS 373.7 (M+H)*

Example 124 {5-Met±iyl-2H-pyrazol-3-yl) - (2-pheii,ylainino-
5,6,7, 8-tetraliydroquinazol±nin-4-yl) -amine (IIc-45) :

Prepared in a manner similar to the above described
Method C.

Example 125 [2- (Biphenyl-3-ylainino) -quinazolin-4-yl] - (5-
cyclopropyl-2H-pyrazbl-3-yl) -amine (IIc-46) : Prepared in
a manner similar to the above described Method A to
afford a pale brovm solid, mp ISSOC; NMR (DMSO) 5 0.73

IS (2H, s), 0.90 {2H, d) , 1.89 (IH, m) , 5.83 and 6.70 (IH,
br s, rotamers) , 7.25 (2H, d) , 7.32 (2H, m) , 7.50 (3H,
t), 7.68 (3H, m), 8.00 (IH, d) , 8.22 (IH, br s) , 8.40
(IH, br s) , 9.20 and 9.89 (IH, br s, rotamers), 10.06 and
10.46 (IH, s, rotamers), 12.17 and 12.84 (IH, br s,

20 rotamers); IR (solid) 3333, 1627, 1609, 1581, 1540, 1504,
1472, 1449, 1426, 1335, 1248, 1216, 1102, 988, 819; MS
419.3 (M+H)*

Example 126 (5-Cyclopr<^yl-2£r-pyrazol-3-yl) - [2- (3-
25 pbenylpr^-l-ylamino) -quinazolin-4-yl] -amine (llc-47) :
Prepared in a manner similar to the 5±>ove described
Method A to afford a white solid, rap 189»C.; ^H NMR (DMSO)
5 0.71 (2H, s), 0.91 (2H, s), 1.89 (3H, s) , 2.69 (2H, s) ,
3.37 (2H, s) , 5.76 and 6.66 (IH, br s, rotamers), 6.95-
30 7.60 (8H, m) , 8.10-8.40 (IH, m) , 9.89 and 10.30 (IH, br
s, rotamers) , 12.10 and 12.75 (IH, br s, rotamers); IR
(solid) 1622, 1595, 1572, 1545, 1499, 1481, 1417, 1390,
1367, 1048, 997, 829; MS 385.4 (M+H)*

Vv

V

-270-

Example 127 [2 - (4 -acetamido-3 -methylphenylamino) -
qulnazolin-4 -yl] - (5-iiiethyl-2flr-pyrazol-3 -yl) -amine
(IXc-48) : Prepared in a manner similar to the above
5 described Method- A to-af ford a pale brovm solid, vap
■ 2S1«C; NMR (DMSO) 5 2.04 (3H, s) , 2.19 {3H, s) , 2.56
(3H, s) , 5.92 and 6-80 (IH, br s, rotamers) , 7.22 (2H,
S), 7.48 (IH, S), 7.64 (IH, s) , 7.73 (2H, s) , 8.40 (IH,
s) , 9.05 and 9.74 (IH, br s, rotamers), 9.20 (IH, s) ,
10 10.05 and 10.54 (IH, br s, rotamers), 12.15 and 12.82

(IH, br s, rotamers); IR (solid) 3309, 2972, 2936, 1641,
1604, 1577, 1536, 1504, 1468, 1423, 1409, 1377, 1341,
1304, 1259, 1223, 1100, 1009, 864; MS 388.2 (M+H) *

15 Example 128 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (indan-2-
ylamino) -quinazolin-4-yl] -amine (IIc-49) : Prepared in a
manner similar to the above described Method A to afford
a brown solid, mp 233-234°C; NMR (DMSO) S 0.65 (2H, s) ,
0.84 (2H, s) , 1.83 (IH, s) , 2.91 (2H, m) , 3.33 (2H, s) ,

20 4.72 (IH, s) , 6.07 (IH, br s) , 7.00-7.60 (8H, m) , 8.29
(IH, s), 10.30 (IH, br s), 12.24 (IH, br s) ; IR (solid)
3425, 2941, 2836, 1622^/ 1595, 1572, 1540, 1495, 1476,
1426, 1394, 1248, 1025, 1007, 870, 833; MS 383.3 (M+H)*

25 Example 129 [2- O-Methylphenylamino) -quinazolin-4-yl] - (5-
methyl-2H-pyrazol-3-yl) -amine < lie- 50 ): Prepared in a
manner similar to the above described Method A to afford
an off-white solid, mp 240-242<»C; ^H NMR (DMSO) S 2.25
(3H, S) , 2.30 (3H, s) , 5.95 (IH, br s) , 6.76 (lH, d),

30 7.10-7.35 (2H, m) , 7.48 (IH, s) , 7.55-7.85 (3H, m) , 8.40
(IH, s) , 9.05 and 9.74 (IH, br s, rotamers) , 10.07 and
10.55 (IH, br s, rotamers), 12.14 and 12.81 (IH, br s.

-271-

rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549,
1536, 1461, 1445, 1408, 1372, 1330,. 1267, 1239, 1184,
1166, 113&, 993, 838, 806; MS 331,3 (M+H)*

5 Example 130 [2- (2-Chloro-5-methylplienylamino) -quinazolin-
4-yll - (5-methyl-2Ji-pyrazol-3-yl) -amine (IIc-51) : Prepared
in a maimer similar to the above described Method A to
afford a grey solid, 246-247<»C; NMR (DMSO) 5 2.19
(3H, s) , 2.31 (3H, s) , 6.37 (IH, br s) , 6.94 (IH, d) ,
10 7.23 (IH, s), 7.37 (IH, d) , 7.43 (IH, d) , 7.64 (IH, t) ,
7.97 (IH, s), 8.19 (IH, s) , 8.42 (IH, br s) , 10.17 (IH,
br s>, 12.19^ (IH, br s) ; IR (solid) 3409, 2918, 2850,
1627, 1591, 1573, 1545, 1513, 1486, 1463, 1418, 1386,
1332, 1291, 1259, 1182, 1000, 827; MS 365.2 (M+H) *

15

Example 131 (5-Cyclopropyl-2H-pyra201-3-yl) -{2- [4-
(mprpholin-l-yl)phenylaminol -quinazplin-4-yl}-ainine
(ZZc-52) : Prepared in a manner similar to the above
described Method A to afford a grey solid, mp 275-276°C;

20 ^H NMR (DMSO) ,5 0.71, (2H, s) , 0.90 (2H, s) , 1.89 (IH, s) ,
3.05 (4H, S), 3.75 (4H, s) , 5.78 and 6.61 (IH, br s,
rotamers) , 6.93 (2H, s) , 7-20 (IH, s) , 7.43 (IH, s) ,
7.50-7.90 (3H, m) , 8.39 (IH, s) , 8.95 and 9.58 (IH, br s;
rotamers), 10.07 and 10.47 (IH, br s, rotamers), 12.16

25 and 12.81 (IH, br s, rotamers); IR (solid) 3245, 2990,
2972, 2959, 2936, 2918, 1618, 1577, 1559, 1509, 1477,
1445, 1413, 1382, 1264, 1223, 1150, 1109, 1050, 923, 882,
823; MS 428.3 (M+H)*

30 Example 132 [2- (Benzothiazol-6-ylainino) -qainazolin-4-yll -
(5-methyl-2H-pyrazol-3-yl) -amine (Ilc-53) : Prepared in a
manner similar to the above described Method A to afford
an off-white solid, mp 236-239'>C; ^H NMR (DMSO) 6 2.25

-272-

(3H, s), 6.35 (IH, br s) , 7.22 (IH, t) , 7.53 (IH, d) ,
7.62 (IH, t), 7.76 (IH, d) , 7.98 (IH, d) , 8.39 (IH, d) ,
9.05 (IH, s) , 9.17 (IH, s) , 9.59 (IH, br s) , 10.30 (IH,
br S), 12.35 (IH, br s) IR (solid) 1622, 1605, 1567,
5 1546, 1505, 1473,-1441, 1417> 1385, 1341, 1297, 1273,
1253, 1192, 1130; MS 374.1 (M+H)*

Example 133 [2 - ( 3 , 4 -Dimetliylphenylaialno) -quinazolin- 4 -■
yl] - (5-methyl-2H-pyrazol-3-yl) -aanine (IIc-54) : Prepared

10 in a manner similar to the above described Method A to
afford an off-white solid, rap 249-2510C; ^H NMR (DMSO) 5
2.18 (3H, br s) , 2.21 (3H, br s) , 2.24 (3H, br s) , 5-92
and 6.80 (IH, 2 x br s) , 7.05 (IH, br s) , 7.21 (IH, br
s) , 7.46 (IH, br s) , 7.64 (3H, br s) , 8.37 (iH, br s) ,

15 9.00, 9.51 and 9.73 (IH, 3 x br s) , 10.12, 10.54 and

12.17 (IH, 3 X br s) ; IR (solid) 1616, 1582, 1547, 1505,
1473, 1452, 1413, 1368, 1334, 1294, 1246, 1210, 1188,
1170, 1139; MS 345.3 (M+H) *

20 Example 134 [2- O-Ethylphenylamino) -quinazolin-4-yl] - (5-
methyl-2H-pyxazol-3-yl) -amine (IIc-55) : Prepared in a
maimer similar to the above described Method A to afford
an off-white solid, mp 238-239«»C; ^H NMR (DMSO) 5 1.21
(3H, t), 2.25 (3H, br s) , 2.61 (2H, q) , 5.92 and 6.80

25 (IH, 2 X br S), 6.78 (IH, d) , 7.21 (2H, br s) , 7.48 (IH,
br s), 7.65 (IK, S), 7.72 (IK, s) , 7.80 (IH, s) , 8.40
(IH, br s) , 9.09, 9.58 and 10.10 (IH, 3 x br s) , 10.54,
12.26 and 12.81 (IH, 3 X br s) ; IR (solid) 1619, 1556,
1535, 1471, 1441, 1407, 1377, 1341, 1274, 1246, 1185,

30 1167, 1139, 995; MS 345.5 (M+H)*

Example 135 [2 - (3 -Methoxyphenylamino) -quinazolin-4 -yll -
(5-methyl-2H-pyrazol-3-yl) -amine (Ilc-56) : Prepared in a

i

-273-

marmer similar to the above described Method A to afford

an off-white solid, mp 212-215»C; NMR (DMSO) 8 2.25
(3H, br s) , 3.77 (3H, s) , 5.92 and 6.84 (IH, 2 x br s) ,

6.55 (IH, d) , 7.13 {2H, .m), 7.41-7.50 (2H, m) , 7.65 (IH,
5 s), 7.77 (IH, s), 8.41 (IH, br s) , 9.10, 9.79 and 10.10
(IH, 3 X br s), 10.55, 12.13 and 12.82 (IH, 3 x br s) ; IR
(solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277,

1256, 1201, 1159; MS 347.4 (M+H) *

IQ Example 136 [2- {4-Acetaiiiido<-3-cyanophenylaiBino) -
«Iuinazoliii-4-yl] - (5-iaethyl-2H-pyrazol-3-yl) -amine
(11c- 57) ; Prepared in a manner similar to the above
described Method A to afford an off-white solid, mp 294-
2960C; =^H NMR (DMSO) 5 2.08 (3H, s) , 2.28 (3H, s) , 6.67

15 (IH, br s) , 7.27 (IK, s) , 7.43 (IH, d) , 7.53 (IH, s) ,

7.68 (1H,.S), 8.04 (IH, d) , 8.45 (2H, s) , 9.41, 10.35 and
12.18 (2H, 3 xbr s>, lO.OO (IH, s) ; IR (solid) 1620,
1583, 155a, 1237, 1508, 1477, 1446, 1413, 1373, 1341,
1292, 125&, 1241, 1180, 1162, 1142, 1105, 1030, 1000; MS

20 399.2 (M+H)*

Example 137 [2 - ( 2 -Methoxybiphenyl - 5 -ylamino) -quinazolin-
4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (llc-58) : Prepared
in a manner similar to the above described Method A to

25 afford a white solid, 222-223 'C; ^H NMR (DMSO) 6 2.22 (3H,
S), 3.75 (3H, s), 6.82 (IH, br s) , 7.05-7.11 (IH, m) ,
7.15-7.25 (IH, m), 7.30-7.36 (IH, m) , 7.40-7.50 (3H, m) ,
7.49-7.55 (2H, m) , 7.55-7.70 (IH, m) , 7.70-7.82 (IH, m) ,
7.90-8.02 (IH, m), 8.30-8.50 (IH, m) ; IR (solid) 1625,

3-0 1604, 1574, 1556, 1496, 1473, 1444, 1403, 13 84, 1258,
1234., 1182, 1018 , 824 , 806 , 755, 698; MS 423.4 (M+H)*

-274-

Example 138 [2 - (4 -Acefcamidophenylamino) -quinazoliii-4 -yl] -
(5-met:liyl-2H-pyrazol-3-yl) -amine (Ilc-59) : Prepared in a
maimer similar to the above described Method A to afford
an off-white solid, mp 253-256»C; ^ NMR (DMSO) 5 2 . 02
5 (3H, s.) , 2.25 {3H, br s) , 5.92 and 6.77 (IH, 2 x br s) ,
7.21 (IH, s), 7.49 {3K, s) , 7.63 (IH, s) , 7.83 (2H, d) ,
8.38 (IH, br s) , 9.03 and 10.05 (IH, 2 x br s) , 9-81 (IH,
s) , 12.13 and 12.80 (IH, 2 x br s) ; IR (solid) 1669,
1635, 1617, 1574, 1535, 1512, 1486, 1422, 1394, 1366,
10 1:J16, 1268, 1231, 1184, 1119, 1101; MS 374.1 (M+H)*

Example 139 [2 - (4 r tert-Butoxycsurbonylamino-phenylamino) -
<Iuinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine
(IIe-60): Prepared in a manner similar to the above

15 described Method A to afford an off-white solid, mp 238-
242"»C; NMR (DMSO) 5 1.48 (9H, s) , 2.24 (3H, s) , 6.23
(IH, brs), 7.1.2 (IH, s) , 7.36 (3H, s) , 7.54 (IH, s) ,
7.67 (2H, d) , 8.30 (IH, d) , 9.14 (2H, br s) , 10.24 and
12.19 (IH, 2 X br s>; IR (solid) 1698, 1620, 1555, 1520,

20 1475, 1443, 1405, 1371, 1310, 1241, il67, 1055, 996; MS
432.1 (M+H)*

■■■-J ■ .

Example 140 [2- (4-Cyeui<^henylajiiino) -qiiinazolin-4-yl] - (5-
iaethyl-2H-pyrazol-3-yl)-amine (llc-61) : Prepared in a

25 manner similar to the above described Method A to afford
an off-white solid, mp 293-298«C; ^H NMR (DMSO) 6 2.25
(3H, s) , 6.50 (IH, br s) , 7.27 (IH, s) , 7.51 (IH/ s) ,
7.64 (IH, s) , 7.71 (2H, d) , 8.40 (IH, s) , 9.76 (IH, br
s) , 10.34 (IH, br s) , 12.33 (IH, br s) ; IR (solid) 1633,

30 1605, 1571, 1517, 1505, 1469, 1418, 1337, 1255, 1174,
1000; MS 342.1 (M+H) *

»

-275-

Example 141 (5-Methyl-2H-pyrazol-3-yl) - C2- (6-0x0-6, 10b-
dihydro-4aH-benzo [c] chrQiaen-2-ylaialno) -quixiazolin-4-ylj[ -
amine (lIc-62) : Prepared in a manner similar to the above
described Method A to afford a pale yellow solid, mp 293-
& 298<»C; ^ NMR (DMSO) 5 1.72 (3H, br s) , 6.23 (IH, br s) ,
7.5a (IH, t) , 7.66 (2H, t) , 7.75 (IH, t) , 7.87 (IH, t) ,
7.77 (IH, t) , 8.26 (IH, d> , 8.33 (IH, d) , 8.58-8.72 (2H,
m), 10.55 (IH, s), 11.55 (IH, s), 12.40 (IH, s) ; IR
(solid) 1707, 1629, 1607, 1579, 1540, 1497, 1488, 1471,
10 1446, 1428, 1417, 1346, 1332, 1298, 1270, 1255, 1207,

1114, 998, 816, 793, 766, 758, 710, 685; MS 435.4 (M+H) *

Example 142 [2- (Biphenyl-3-ylamino) -quinazolin-4-yl] - (5-

methyl-2H-pyrazol-3-yl) -amine (IIc-63) : Prepared in a
15 manner similar to the above described Method A to afford

a pale brown solid, rap 206-207"»C; ^H NMR (DMSO) 5 2.20
(3H,S), 6.80 (IH, br s) , 7.24-7.27 (2H, m) , 7.36-7.40
(2H, m) , 7.48-7.52 (3H, m) , 7.67-7.69 (3H, m) , 7.94 (IH,

m) , 8.26 (IH, m) , 8.42 (IH, m) , 9.30 (IH, br s) , 10.16
20 (IH, br s), 12.13 (IH, br s) ; IR (solid) 1593, 1578,.

1544, 1498, 1479, 1414, 1384, 1251, 1209, 1003; MS 393.2
(M+H)*

Example 143 [2 - ( 4 -Methoxycarbonylme thyl - 3 -
25 methylphenylamino) -qniinazolin-4-yl] - (5-methyl-2fl-pyrazol-
3_yl)-amine (lIc-64) : Prepared in a manner similar to the.
above described Method A to afford a white solid, mp 245-
246°C; ^H NMR (DMSO) 5 2.23 (3H, s) , 2.26 (3H, s) , 3.63
(3H, s) , 3.64 (2H, s) , 5.99 (0.5H, br s) , 6.80 (0.5 H, br
30 s) , 7.10 (IH, m) , 7.25 (IH, m) , 7.50 (IH, m) , 7.61-7.80
(3H, m) , 8.44 (IH, m) , 9.10 (0.5H, br s) , 9.78 (0.5H, br
S) , 10.11 (0.5H, br s), 10.56 (0-5H, br s) , 12.18 (0.5H,

3

-276-

br s), 12.90 (0.5H, br s) ; IR (solid) 1732, 1710, 1622,

1581, 1554, 1538, 1508, 1490, 1446, 1411, 1371, 1336,

1306, 1257, 1244, 1204, 1146, 1016, 998, 797, 754, 692;

MS 403.4 (M+H)*

5

Example 144 [2- (4-Carboxymethyl-3-methylplienylamino) -

qttinazolin-4-yl] - (5-iaethyl-2H-pyrazol-3-yl) -amine
(IIc-65) : A solution of [2- (4-methoxycarbonylmethyl-3-
methylphenylami^o) -quinazolin-4-yl] - (5 -methyl -2H-pyrazol-

10 3-yl) -amine (IIc-64, 200 mg, 0.5 mmol) in a mixture of
methanol /water (3/1, 8 mL) was treated with IM NaOH (2
mL, 2 mmol) . The mixture was heated at 70 »C. for 2 hours
and then neutralised with IM HCl {2ml., 2 mmol) . The
solid that formed was collected by filtration to afford

15 the title compound (185 mg, 95%) as a pale yellow solid,

mp 245'»C (dec); NMR (DMSO) 5 2.27 (6H, 2xs) , 3.55 (2H,
S), 6.49 (IH, S), 7.13 (IH, d) , 7.26 (IH, t) , 7.50 (IH,
d), 7.62-7.78 (3H, m) , 8.42 (IH, d) , 9.34 (lH,d), 10.26
(IH, S), 12.-36 (IH, s); IR (solid) 1660, 1E90, 1562,

20 1504, 1427, 1385, 810, 776, 751, 693; MS 389.4 (M+H) *

Example 145 [2- (4-Amlnoplienylamino) -cnainazolin-4-yl] - (5-
lnethyl-2H-pyrazol-3-yl) -amine (IIc-66) : A solution of [2-
(4 - tert -Butoxycarbonylamino-phenylamino) - quinazolin- 4 -

25 yi]-(5-methyl-2H-pyrazol-3-yl) -amine (IIc-60, 100 mg,
0.232 mmol) in a mixture of DCM/TFA (5/1, 12 mL) was
stirred for 2 hours at room temperature. The solvents
were removed in vacuo and the residue triturated in
aqueous K2CO3. The resulting solid was collected by

30 filtration and washed with diethyl ether to afford lie- 66
(69 mg, 90%) as an off-white solid, mp 164-167-C; ^H NMR
(DMSO) 5 2.24 (3H, s) , 6.33 (IH, br s), 7.12 (2H, d) ,
7.48 (3H, m), 7.58 (IH, d) , 7.86 (IH, t) , .8.64 (IH, d) ,

-277-

10.86 (IH, br s) , 11.46 (IH, s) ; IR (solid) 1681, 1512,
1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H) "*■

Example 146 [2- (4-Broiiiophenylainino) -quinazolixi-4-yl] - (5-
5 inethyl-2H-pyrazol-3-yl) -aiBiae -(Ilc-67) : Prepared in a
manner similar to the above described Method A to afford
an off-white solid, mp 290-293OC; NMR (DMSO) 5 2.27
(3H, s) , 6.71 (IH, br s) , 7.22 (IH, m) , 7.46-7.50 (3H,
m) , 7.66 (IH, m) , 7.92-7.94 (2H, m) , 8.38 (IH, m) , 9.28,
10 ■ 10.11 and 12.13 (3H, 3 X br s) ; IR (solid) 1619, 1572,
1548, 1486, 1436, .1409, 1372, 1238, 1186, 1136, 1071,
997; MS 395.1/397.1 (M+H)*

Example 147 [2- (4-Isobutyrylainino-phenylamino) -
15 quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIc-
68) : Prepared in a manner similar to the above described
Method A to afford a yellow solid, mp 176-179°C; NMR
(DMSO) 5 1.11 (6H, d>, 2.15 {3H, s) , 2.62 (IH, m) , 6.25
(IH, br s), 7.41 (IH, d), 7.46 (IH, t) , 7.63 (IH, d) ,
20 7.71 (2H, d) , 7.84 (IH, t) , 8.64 (IH, d) , 10.00 (IH, s) ,
10.34 (IH, br s), 11.47 (IH, br s) , 12.47 (IH, br s) ; IR
(solid) 1676, 1653, 1585, 1561, 1512, 1423, 1407, 1312,
1199, 1177, 1128; MS 402.3 (M+H)*

25 Example 148 (5-Bthyl-2H-pyrazol-3-yl) - [2- (5-ethyl-2H-

pyrazol-3-ylamino) -guinazolin-4-yli -amine <IXc-69) : To a
solution of 2,4-dichloroquinazoline (O.Sg, 2.51mmol) and
3-amino-5-ethylpyrazole (558 mg, 5.02 mmol) in ethanol
(lOmli) was added triethylamine (0.35mL, 2.51mmol) and the

30 resulting mixture was stirred for 3 hours at room

temperature. The resulting pale yellow precipitate was
collected by filtration, washed with cold ethanol and
dried under vacuum to afford Ilc-69 (306 mg, 35%) as an

-278-

aff-wlHtte solid, mp 248-252'»C; NMR (DMSO) 5 1.30 (m,
6H), 2.72 (m, 4H) , 6.12 (br.s, IH) , 6.54 and 6.90 (br. s,
IH), 7.58 (t, IH), 7.74 (d, IH) , 7.90 (t, IH) , 8.78 (d,
IH) ; IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2
5 (M+H)*

Example 149 (lH-Indazol-3-yl) - (2-phenylamillo-quinazolin-
4-yl) -amine {IIc-70) : Prepared in a manner similar to the
above described Method A to afford a white solid; NMR
10 (DMSO) 5 6.90 (m, 3H) , 7.11 (t, IH) , 7.19 (m, 2H) , 7.44
(t, IH) , 7.57 (m,. IH), 7.62 (d, IH) , 7.67 (d, 2H) , 7.71
(d, IH), 7.93 (t, IH), 8.59 (d, IH) , 11.55 (br. s, IH) ,
13.15 (s, IH) ; MS 353.2 (M+H) *

15 Example 150 (lH-Indazol-3-yl) - [2- (3-

trifluoromethylpheiiylami.no) -quinazolin-4-yll -amine
(llc-71) : Prepared in a manner similar to the eJDOve
described Method A to afford a pale yellow solid. ^H NMR
(DMSO) 6 7.00- (t, IH), 7.02 (d, IH) , 7.22 (d, IH) , 7.37

20 (td, IH), 7.56 (m, 3H) , 7.61 (d, IH) , 7.66 (d, 2H) , 7.92
(t, IH) , 8.60 (d, IH) , 10.61 (br. s, IH) , 11.42 (br. s,
IH) , 13.12 (s, IH); MS 421.2 (M+H)*

Example 151 (lH-Indazol-3-yl) - [2- (4-
25 trifluoromethylphenylamino) -quinazolin-4-yl] -amine
(lie -72) : Prepared in a manner similar to the above
described Method A to afford a pale yellow solid. ^H NMR
(DMSO) 5 7.08 (t, IH) , 7.16 (d, 2H) , 7.44 (m, 3H) , 7.58
(t, IH) , 7.6 (t, 2H), 7.69 (d, IH) , 7.95 (t, lH), 8.62
30 (d, IH), 10.82 (br. s, IH), 11.50 (br. s, IH) , 12.20 (s,
IH) ; MS 421.2 (M+H)*

10

-279-

Bxample 152 [2- (Adaiiiantdn-2-ylaiiiino) -quinazolin-4-yl] -
(lH-iiidazol-3-yl) -amine (ilc-73) : Prepared in a manner
similar to the above described Method A to afford a white
solid. NMR (DMSO) 5 0 . 83 (br. s, IH) , 0.85 (br. S, IH) ,
1.44 (m, 4H) , 1.55 (m, ' 3H) , 1.63 (s, 2H) > 1.73 (s, IH) ,

I. 82 (s, IH) , 1.84 (s, IH) , 3.56 (m, IH) , 7.10 (t, IH) ,
7.41 (t, IH), 7.51 (t, IH), 7.54 (d, IH) , 7.57 (d, IH) ,
7.69 (d, IH) , 7.a0 (t, IH), 8.45 (d, IH) , 8.58 (d, IH) ,

II. 60 (S, IH), 13.10 (S, IH) ; MS 411.3 (M+H)*

Example 153 (lH-Indazol-3-yl) - (2-meth.yl-phenyl-alnino-
quiIlazolin-4-yl) -amine (llc-74) : Prepared in a manner
similar to the above described Method A to afford a white
solid; NMR (DMSO) 6 3.27 (s, IH) , 6.88 (t, IH) , 6.93
15 (t, 2H), 7.04 (t, IH), 7.14 (d, 2H) , 7.22 (t, IH) , 7.36
(m, 2H), 7.48 (d, IH) , 7.54 (d, IH), 7.62 (t, IH) , 8.37
(d, IH), 10.11 (s, IH), 12.71 (S, IH) ; MS 367.2 (M+H)*

Example 154 [2- (2-Chloro-phenyl) -amino-quinazolin-4-yl] -
20 (lH-indazol-3-yl) -amine (Ilc-75) : Prepared in a manner

similar to the aiaove described Method A to afford a white
solid. ^H NMR (DMSO) 6 6.81 (t, IH) , 6.87 (td, IH) , 7.07
(t, IH), 7.34 (dd, IH), 7.35 (t, IH) , 7.40 (t, IH) , 7.53
(d, IH), 7.56 (d, IH), 7.63 (d, 2H) , 7.72 (t, IH) , 8.07
25 (d, IH) , 8.46 (d, IH) , 10.37 (s, IH) , 12.89 (s, IH) ; MS
387.1 (M+H)*

Example 155 (lJff-lndazol-3-yl) - C2- (2-

trif luoromethylphenylamino) -qiiinazolin-4-ylI -amine (IIc-
30 76) : Prepared in a manner similar to the above described
Method A to afford a white solid; ^H NMR (DMSO) 8 7.01 (t,
IH), 7.20 (m, IH), T.32^ (m, IH) , 7.36 (t, IH) , 7.43 (d.

-280-

1H>, 7.49 (d, 1H>, 7.55 (d, IH) , 7.61 (t, IH) , 7.64 (d,
IH), 7.69 (d, IH), 7.95 (t, 2H) , 8.62 (d, IH) , 10.15 (m,
IH), 11.62- (S, IH), 13.03 (S, IH); MS 421.2 (M+H)*

5 Example 156 [2- (4-Cyauaojaethylpbenylamino) -quinazolin-4-
yl] - (lH-indazol-3-yl) -amine {lIc-77) 8 Prepared in a
manner similar to the above described Method A to afford
a white solid; NMR (DMSO) 5 13.16 (s, IH) , 11.49 (br.
s, IH), 10.38 (br. s, IH)-, 8.58 (d, IH) , 7.92 (t, IH) ,
10 7.67 (t, 2H) , 7.61 (d, IH) , 7-56 (m, IH) , 7.44 (t, IH) ,
7,22 (m, 2H), 7 . 0« (t, IH) , 6.86 (m, 2H) , 3.87 (s, 2H) ;
MS 392.2 (M+H)*.

Example 157 [2- (4 -Chlorophenylamino) -5,6,7,8-
15 tetrahydroqruinazolinin-4-yl] - (5-methyl-2H-pyrazol-3 -yl) -
amine (lIc-78) : Prepared in a manner similar to the above
described Method C; MS 355.5 (M+H)*

Example 158 (5-Methyl-2H-pyrazol-3 -yl) - (2 -phenylaru.no-
20 6,7,8,9-tetrsdjydro-5H-cycloheptapyrimidin-4-yl) -amine
(lIc-79) » Prepared in a manner similar to the above
1) described Method C; MS 335.3 (M+H)*

Example 159 [2- (Benzimidazol-2-ylamino) -7-benzyl-5,6,7,8-
25 tetrahydro-pyrido [3 , 4-d] pyrimidin-4 -yl] - (5 -methyl-2H-
pyrazol-3-yl) -amine (IIc-80) : Prepared in a meuiner
similar to the above described Method C; MS 452.0 (M+H)*

Example 160 (7-Benzyl-2-phenylamino-5,6,7, 8-tetrahydro-
3a pyrido [3,4-d]pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) -
amine (lie- 81) s Prepared in a manner similar to the above
described Method C; MS 412.1 (M+H)*

10

15

-281-

Example 161 [6 -Benzyl - 2 - ( 4 -chlorophenylamino) -5,6,7,8-
tetrahydro-pyrido[4,3-d] pyriiiiidin-4-yl] - ( 5 -methyl - 2H-
pyrazol-3-yl) -amine (IIc-82) s Prepared in a manner
similar to the above described Method C; MS 446.3 (M+H>*

Example 162 [2- (Benzlmidazol-2-ylamJ.no) -6-benzyl-S, 6,7, 8-
tetrah.ydro-pyrido C4,3-d]pyrimidin-4-yl] - ( 5 -methyl - 2H-
pyrazol-3-yl) -amine (XIc-83) s Prepared in a manner
similar to the above described Method C; MS 452.2 (M+H)*

Example 163 ( 6 - Benzyl - 2 -phenylamino- 5,6,7,8 - te trahydro -
pyrido [4,3-dJpyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) -
amine (llc-84) : Prepared in a manner similar to the above
described Method C; MS 411.9 (M+H)* .

Example 164 (5-Methyl-2JH"-pyrazol-3-yl) - ( 2 -phenylamino -
5, 6,7, 8- te trahydro -pyrido [3 , 4-d] pyrimidin-4-yl) -amine
(IIc-85) : Prepared in a manner similar to the above
described^ Method C; MS 322.3 (M+H)*

Example 165 [2 - (4 -Cyanomethylphenylamino) - quinazolin- 4 -
yl] - (IH-pyrazolo [3,4 -b]pyridin-3-yl) -amine (IIc-86) :
Prepared in a manner similar to the above described
Method A to^ afford an off-white solid; NMR (DMSO) 6
13.65 (s, IH), 12.82 (br. s, IH) , 11.69 (br. s, IH) , 8.55
(dd, 2H), 8.12 (d, IH), 7.88 (m, IH) , 7.66 (m, IH) , 7.50
(m, IH), 7.30 (m, 2H), 7.09 (m, IH) , 6.94 (m, 2H), 3.89
(s, 2H>; MS 393.1 (M+H)*.

3 0 Example 166 [2^(4 -Cyanob^zylamlno) - quinazolin- 4 -yl] - ( IH-
pyrazolo[3,4-b]pyridin-3-yl)-amine (IIc-87) : Prepared in
a manner similar to the above described Method A to
afford an off-white solid; ^ NMR (DMSO) 8 13.68 (s, IH) ,

20

25

-282-

12.82 (br. s, 1H)> 11.70 (br. S, IS), 8.55 (m, 3H) , 8.00
(d, IH), 7.92 (t, IH), 7.59 (m, 4H) , 6.96 (m, 2H) , 6.86
(m, IH) , 4.23 (s, 2H) ; MS 393.1 (M+H)*.

5 Example 167 [2- (4-Gyaaoimethylphenylamixio) -qu±nazolin-4-
yl] - (4-f luoro-lfl-indazol-3-yl) -aiaine (IIc-88) : Prepared
in a manner similar to the above described Method A to
afford a white solid; NMR (DMSO) 5 13.49 (s, IH) , 11.61
(br. s, IH) , 10.64 (br. s, IH) , 8.56 (d, IH) , 7.95 (t,
10 IH), 7.67 (d, IH), 7.58 (t, IH) , 7.46 (t, IH) , 7,43 (dd,
IH), 7.14 (m, 2H), 6.85 (dd, 3H) , 3.88 (s, 2H) ; MS 410.1
(M+H)*.

Example 168 [2- (4-Cyanophenylamino) -qiiinazolin-4-yl] - (IH-
indazol-3-yl) -amine (lIc-89) : Prepared in a manner
similar to the above described Method A to afford a white
solid; =^H NMR (DMSO) 5 13.14 (s, IH) , 11.31 (br. s, IH) ,
10.51 (br. s, IH), 8.59 (d, IH) , 7.91 (t, IH) , 7.65 (d,
3H), 7.56 (t, IH), 7.50 (m, 2H) , 7.45 (dd, IH) , 7.26 (d,
2H), 7.08 (t, IH); MS 378.2 (M+H)*.

Example 169 [2- (4-Cyan6benzylaniino) -ctuinazolln-4-yl] - (IH-
indazol-3-yl) -amine (lie- 90) : Prepared in a manner
similar to the above described Method A to afford a white
solid; ^H NMR (DMSO) 5 13.12 (s, IH) , 12.91 (br. s, IH) ,
11.60 (br. s, IH), 8.57 (d, IH) , 7.91 (t, IH) , 7.63 (d,
IH), 7.55 (m,5H), 7.38 (t, IH) , 6.89 (t, IH) , 6.84 (br.
d, 2H), 4.19 (S, 2H) ; MS 392.2 (M+H)*.

30 Example 170 (5-Cyclopropyl-2H-pyrazol-3-yl) - t2-

(naphthalen-2-yloxy) -quina2olin-4-yll -amine (IIb-1) :
Prepared in a manner similar to the above described

15

20

25

-283-

Method B to afford a white solid, mp 327-328«>C; NMR
(DMSa) 8 -0.05-0.07 (2H, m) , 0.50-0.68 {2H, m) , 1.28-1.40
(IH, m) , 5.68 (1H,S) , 7.40-7.50 (2H, m) , 7,50-7.64 (3H,
m) , 7.70-7.80 {2H, m) , 7.82-8.08 (3H, m) , 8.64 (lH,d) ,
5 10.58 (IH, s) , 12.07 (IH, s) ; IR (solid) 1621, 1595,
1575, 1554, 1508, 1480, 1410, 1385, 1320, 1254, 1240,
1212, 1166, 830, 81&, 758; MS 394.4 (M+H)*

Example 171 (5-Metliyl-2H-pyrazol-3-yl) - t2- (naphthalen-2-
10 yloxy) -quinazolin-4-yl] -amine (IIb-2) : Prepared in a

manner similar to the above described Method B to afford
a. pale brown solid, mp >300<'C; NMR (DMSO) 5 1.62 (3H,
s) , 5.65 (IH, s) , 7.96 (2H, br s) , 7.55 {3H, d) , 7.76
(2H, m) , 7.92 (IH, d) , 8.00 (2H, m) , 8.58 (IH, d) , 10.56
15 (IH, S) , 11. 9& (IH, S) ; IR (solid) 1625, 1601, 1571,
1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159; MS
368.7 (M+H)*

Example 172 (5-Methylr2H-pyrazol-3-yl) - (2-phenoxy-
20 quinazolin-4-yl) -aioaine (IIb-3) : Prepared in a manner

similar to the above described Method B to afford a tan
solid, rap 287-2S0«»C; NMR (DMSO) 6 2.10 (3H, s) , 5.92
(IH, s) , 7.23 (2H, d), 7.29 (IH, t) , 7.38 (IH, t) , 7.46-
7.53 (3H, m) , 7.85 (IH, t) , 8.58 (IH, d) , 10.55 (IH, s) ,
25 12.11 (IH, S); IR (solid) 1622, 1602, 1572, 1556, 1542,
1477, 1454, 1402, 1373, 1316, 1249, 1200, 1172, 1158; MS
318.3 (M+H)*

Example 173 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (5,6,7,8-
30 tetrediydronaphthalen-2-yloxy) -quiaazolln-4-yl] -amine
(Ilb-4) : Prepared in a manner similar to the above
described Method B to afford a solid, rap 277-279«»C; ^H NMR

-284-

(DMSO) 8 0.40-0.50 (2H, m) , 0.89-0.96 (2H, m) , 1.71-1.87
(5H, m) , 2.70-2.83 (4H, m) , 5.88 (IH, s) , 6.88-6.96 (2H,
m) , T.12 (IH, d) , 7.39 (lH,t), 7.58 (IH. d) , 7.76 (IH,
t) , 8.58 (IH, d), 10.54 (IH, s) , 12.20 (IH, s) ; IR
5 (solid) 1731, 1641, 1614, 1570, 1506, 1495, 1464, 1424,

1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4 (M+H)*

Example 174 (5-Cyclopropyl-2H-pyrazol-3-yl) - 12- (3-
iaethylphenoxy) -quinazolin-4-yll -amine (IIb-5) Prepared

10 in a manner similar to the above described Method B to
afford an off-white solid, mp 283-284«C; NMR (DMSO) 8
0.49-0.53 (2H, m) , 0.89-0.96 (2H, m) , 1.72-1.81 (IH, m) ,
2.40 (3H, S) , 5.82 (IH, s) , 7.03 (IH, d), 7.08 (IH, s) ,
7.15 (IH, d>, 7.35-7.46 (2H, m) , 7.58 (IH, d) , 7.78 (IH,

15 t) , 8.62- (IH, d) , 10.58 (IH, s) , 12.25 (IH, s) ; IR

(solid) 1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319,
1253, 1189, 1158, 997, 842, 789, 763; MS 358.4 (M+H) *

Example 175 12- (S-Methoxyphenoxy) -quinazolin-4-yl] - (5-
20 methyl-2H-pyrazol-3-yl) -amine (Ilb-6) : Prepared in a

manner similar to the above described Method B to afford
a white solid, mp 277-278<»C; ^H NMR (DMSO) 5 2.15 (3H, s) ,
3.78 (3H, S) , 6.00 (IH, s) , 6.77-6.90 (3H, m), 7.30-7.41
(2H, m), 7.52 (IH, d), 7.70 (IH, t) , 8.59 (IH, d) , 10.57
25 (IH, s), 1"2.10 (IH, s) ; IR (solid) 1623, 1603, 1575,
1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142,
1046, 1022, 833, 760; MS 348.4 (M+H)*

Example 176 [2- (3, 4-Diinethoxyphenoxy) -quinazolin-4-yl] - .
30 (5-methyl-2H-pyrazol-3-yl) -amine (IIb-7) : Prepared in a
manner similal: to the above described Method B to afford
an off-white solid, mp 277-278«C; ^H NMR (DMSO) 6 2.09-

-285-

{3H, S) , 3.7a {3H, S), 3.78 (3H, s) , 5.98 (IH, s) , 6.73-
6.77 (IH, m), 6.90 (IH, s) , 7.00 (IH, d) , 7.35-7.45 (IH,
m) , 7.58 (IH, d), 7.70-7.78 (IH, m) , 8.63 (IH, d) , 10.55
(IH, S) , 12.19 (IH, S).; IR (solid) 1626, 1603, 1576,
1557, 1509, 1481, 1436, 1409, 1382, 1372, 1318, 1249,
1227, 1195, 1180, 1158, 1120, 10,29, 965, 835, 803,
767,753; MS 378.4 (M+H) *

Example 177 [2- (Benzo [1,3] dioxol-5-yloxy) -quinazol±n-4-
yl] - (5-iaethyl-2fl-pyrazol-3-yl) -amine (IIb-8) : Prepared in
a manner similar to the above described Method B to
afford an off-white solid, mp 296-299°C (dec); ^H NMR
(DMSO) 6 2.13 (3H, s) , 6.05 (IH, s) , 6.09 (2H, s) , 6.69
(IH, d) , 6.90 (IH, s) , 6.98 (IH, d) , 7.39 (IH, t) , 7.53
(IH, d) , 7.70 (lH,t), 8.58 (IH, d) , 10.59 (IH, s) ; IR
(solid) 1602, 1577, 1538, 1508, 1499, 1481, 1455, 1401,
1377, 1323, 1251, 1241, 1169, 1121, 1038, 1022, 951, 935,
863, 813, 7S2; MS 362.4 (M+H)*

Example 178 [2 - (3 -Methoa^ceurbonylplienoxy ) - quinazolin- 4 -
yl]-(5-iiiethyl-2H-pyrazol-3-yl) -amine (lIb-9) : Prepared in
a manner similar to the above described Method B to
afford an off-white solid, mp 269-270<»C; *H NMR (DMSO) 8
2.05 (3H, s), 3.90 (3H, s) , 5.88 (IH, s) , 7.00-7.90 (7H,
m), 8.50-8.65 (IK, m) , 10.65 (IH, s) ; IR (solid) 1722,
1626, 1605, 1578, 1559, 1507, 1429, 1378, 1317, 1282,
1272, 1255, 1204, 1185, 1096, 1021, 990, 869, 841, 758;
MS 362.4 (M+H)*

Example 179 (5-Cyclopropyl-2£r-pyrazol-3-yl) - (2-
pheno3cymethyl-quinazolin-4-yl) -amine (IId-1) : Prepared in
a manner similar to the above described Method C to
afford a pale yellow solid, mp 265-267«»C; ^H NMR (DMSO) 5

-286-

0.67 (2H, m), 0.93 (2H, m) , 1.87 (IH, m) , 5.19 (2H, s) ,
6.55 (IH, l>r s>, 6.90-7.02 (3H, m) , 7.26-7.30 (2H, tn) ,
7,54 (IH, m) , 7.74-7.83 (2H, m) , 8.61 (IH, m) , 10.45 (IH,
br S) , 12.18 (IH, br S) ; MS 358.4 (M+H)*

Example 180 (2-Benzyloxymethyl-quinazolin-4-yl) - (5-
cyclopropyl-2H-pyrazol-3-yl) -amine (lId-2) : Prepared in a
manner similar to the above described Method C to afford
a white solid, mp 211-213'=>C; ^H NMR (DMSO) 8 0.65 (2H, m) ,
0.90 (2H, m), 1.86 (IH, m) , 4.63 (2H, s), 4.68 (IH, s) ,
6.71 (IH, s), 7.28-7.54 (6H, m) , 7.76-7.81 (2H, m) , 8.61
(IH, m), 10.41 (IH, s>, 12.19 (IH, s) ; MS 372.3 (M+H) *

Example 181 {2-Benzyl-quinazolin-4-yl) - (5-cyclopropyl-2H-
pyrazol-3-yl)-amine (IId-3) : Prepared in a manner similar
to the above described Method D to afford a white solid,
rap 219-221»C; ^H NMR (DMSO) 6 0.66 (2H, m) , 0.95 (2H, m) ,
1.87 (IH, m), 4.11 (2H, S), 6.31 (IH, s) , 7.20-7.50 (6H,
m), 7.71-7.79 (2H, m) , 8.55 (IH, m) , 10.27 (IH, s) , 12.15
(IH, S>; MS 342.7 (M+H) *

Example 182 (5-Cyclbpropyl-2H-pyrazol-3-yl) - (2-methyl-
quinazolin-4-yl)-amine {lId-4) -. Prepared in a manner
similar to the above described Method C to afford a white
solid, rap 289-290«>C; ^H NMR (DMSO) 5 2.31 (3H, s) , 2.71
(3H, S), 6.73 (IH, S), 7.75 (2H, q) , 8.04 (IH, t) , 8.82
(IH, s), 11.94 (IH, s), 12.65 (IH, s) ; IR (solid) 3266,
1636, 1607, 1579, 1479, 1407, 769, 668; MS 240.4 (M+H)*

Example 183 [2- (4-Chlorophenoxymethyl) -6,7, 8, 9-
tetrahydro-5H-cycloheptapyrililidin-4-yll - (5-methyl-2H-
pyrazol-3-yl)-aiBine (IId-5) : Prepared in a manner similar

-287-

to the above described Method C to afford a white solid;

NMR (DMSO) 81.58 (2H, m) , 1.68 (2H, m) , 1.85 (2H, m) ,
2.20 (3H, S) , 2.90 (2H, m) , 3.00 (2H, m) , 5.26 (2H, s) ,
6.15 (IH, s) , 7.15 (2H, d) , 7.40 {2H, d) , 10.25 (IH, br) ;
5 MS 384.3 (M+H)*. ' '

Example 184 [2- (4-Chloroph,enoxymethyl) -5,6,7,8-
tetrahydro-cniinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -
amine (lid- 6) : Prepared in a manner similar to the above
10 described Method C to afford a white solid; NMR (DMSO)
51.80 (4K, m), 2.15 (3H, s> , 2.55 (2H, m obscured), 2.75

(2H, m), 5.25 (2H. s) , 6.12 (IH, s) , 7.08 (2H, d) , 7.35

(2H, d) , 9.80 (IH, br) ; MS 370.2 (M+H)*.

15 Example 185 (5-;Cyelopropyl-2H-pyrazol-3-yl) - t2-

(naphtalen-2-ylsulf auxyl) -6-phenylpyrijttidln-4-yll -amine
(IIIa-1) : Prepared in a manner similar to the above
described Method L to affprd a white solid, mp 233 -234 "C;
NMR (DMSO) 5 0.21 (2H, br s) , 0.56 (2H, br s) , 1.17

2a (IH, br m) , 5.35 (IH, br s) , 7.02 (IH, br s) , 7.49 (3H,

m) , 7.59 (2H, m) , 7.73 (IH, d) , 7.88 (2H, m) , 8.02 (3H, ..^
m) , 8.30 (IH, m), 10.01 (IH, s) , 11.75 (IH, br s) ; IR
(solid); MS 436.7 (M+H)*

25 Example 186 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-

methoxycarbonyl-phenylylsulfanyl) -6-phenylpyrlmidin-4-
yl] -amine (IIIa-2) : Prepared in a manner similar to the
above described Method L to afford a white solid, mp 126-
129<»C; ^H NMR (DMSO) 5 0.52 (2H, m) , 0.87 (2H, m) , 1.69

30 (IH, m) , 3.87 (3H, s) , 5.47 (IH, s) , 7.03 (IH, br s) ,

7.49^ OH, m) , 7. 67 (IH, m) , 7.87 (2H, m) , 7.94 (IH, m) ,

-288-

8.09 (IH, m), 8-23 (IH, m), 10.07 (IH, s) , 11.94 (IH, s) ;
IR (solid>; MS 444.7 (M+H)*

Example 187 (5-C?yclopropyl-2H-pyrazol-3-yl) - [2-
5 (naphtlialen-2-ylsulf anyl) -pyrijaidin-4-yl] -amine (lIIa-3) :

Prepared in a manner similar to the above described
Method I. to afford a white solid, mp 248-250»C; NMR
(DMSO) 5 0.21 {2H, br s) , 0.55 (2H, br s) , 0.94 (IH, br
m), 5.31 (IH, br s) , 6.55 (IH, br s) , 7.57-7.66 (3H, m) ,
10 7.99-8.03 {4H, m) , 8.25 (IH, s) , 9.94 (IH, s) , 11.75 (IH,
br s); IR (solid); MS 360.7 (M+H)*

Example 188 (j5-Cyclopropyl-2H-pyrazol-3-yl) - [5, 6-
dimethyl-2- (naplithalen-2-ylsulf anyl) -pyrixBidin-4-yl3 -

15 amine (Ilia- 4) : Prepared in a manner similar to the above
described Method L to afford a white solid, mp >270«C;
NMR (DMSO) 5 0.14 (2H, d) , 0.45 (2H, d) , 0.78 (IH, s) ,
2.05 (3H, s), 2.27 (3H, s) , 5.26 (IH, s) , 7.60 (3H, d) ,
7.99 (3R, d), 8.21 (IH, s>, 8.66 (IH, s) , 11.60 (IH, s) ;

20 IR (solid) 1560, 1508, 1478, 1288, 1176, 1109, 994, 809,
740, 669; MS 388.7 (M+H)*

Example 189 (5-Cyclopropyl-2H-pyrazol-3-yl) - [5-methyl-2-
(naphthalen-2-ylsulf anyl) -pyrimidin-4-yl] -amine (IIla-5) :

25 Prepared in a manner similar to the above described

Method L to afford a white solid, mp 197 -C; ^H NMR (DMSO)
8 0.21 (2H, d), 0.51 (2H, d) , 0.78 (IH, s) , 2.08 (3H, s) ,
5.40 (IH, S), 7.57 (2H, d) , 7.62 (IH, d) , 7.92 (IH, s) ,
7.97 (3H, d), 8.22 (IH, s) , 8.88 (IH, s) , 11.70 (IH, s) ;

30 IR (solid) 1738, 1583, 1563, 1488, 1460, 1364, 1234,1216,
808, 656; MS 374.2 (M+H)*

10

-289-

Example 190 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-metliyl-2-
(naplithalen-2-ylsulfanyl) -pyrimid±n-4-yl] -amine (Ilia- 6) :
Prepared in a manner similar to the above described
Method L to afford a white solid, rap 232<'C; NMR (DMSO)
5 0.15 (2H, s), 0.51 •(2H, s) , 0.92 (IH, s) , 2.20 (3H, s) ,
5.22 (IH, s.) , 7.60 (2H, s) , 7.67 (IH, d) , 7.98 (3H, s) ,
8.24 (IH, s) , 9.79 (IH, s) , 11.60 (IH, s) ; IR (solid)
1586, 1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666;
MS 374.2 (M+H)*

Exami>le 191 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-
(morpholin-4-yl) -2t (naphthalen-2-ylsulf anyl) -pyrimidin-4-
yl] -amine (IIIa-7) : To a solution of 2,4,6-
trichloropyrimidine (600 mg, 3.27 ramol) and 3 -amino- 5-

15 cyclopropylpyrazole (403 m.g, 3.27 ramol) in EtOH (10 raL)
was added triethylamine (456 |IL, 3.27 ramol) and the
reaction mixture was stirred for 15 hours at room
temperature. The solvent was evaporated and the residue
was purified by flash chromatography (SiOa, Hexane/AcOEt

20 gradient) to afford (5-cyclopropyl-2H-pyrazol-3-yl) - (2 , 6-
dichloropyrimidin-4-yl) -amine (705 mg, 80%).

To a solution of (5-cyclopropyl-2H-pyrazol-3-
yl) - (2,6-dichloropyrimidin-4-yl) -amine (211 mg, 0.781
mmol) and 2-naphthalenethiol (125 mg, 0.781 ramol) in

25 tert-butanoi (5 mL) was added triethylamine (174 jiL, 1.25
ramol) and the resulting mixture was heated at reflux for
15 hours. The reaction mixture was cooled to room
temperature and partitioned between ethyl acetate and
aqueous NaHCOa. The organic layer was washed with brine,

30 dried over MgS04 and concentrated in vacuo. The residue
was purified by flash chromatography (Si02/ Hexane/AcOEt
gradient) to afford [6-chloro-2- (naphthalen-2-

i >

-290-

ylsulfanyl) -pyrimidin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-
yl) -amine.

Tlie above formed t6-chloro-2- {naphthalen-2-
ylsulfanyl) -pyrimidin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-
5 yl) -amine (70 mg, 1.78 .10"* mol) was dissolved in

morpholine (3 mL) and the mixture heated at 120»C for 15
hours. The solvent was evaporated and the residue was
purified by flash chromatography to afford lIIa-7 (50 mg,
63%) as a white solid, mp 118-120®C; NMR (DMSO) 5 0-34-
10 0.91 (4H, 4xm) , 1.28 and 1.78 (IH, 2xm) , 3.32 (2H, m) ,
3.60 (6H, m) , 5.38-6.16 (2H, br m) , 7.55-7.66 (3H, m) ,
7.95-8.02 (3H, m) , 8.19 and 8.23 (IH, 2xs) , 9.28 and 9.31
(IK, 2xbr s) , 11.71 and 11.84 (IH, 2xbr s) ; IR (solid);
MS 445.2 (M+H)*

15

Example 192 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6- (1-
inethylpipera2in-4-yl) - 2- (naphthalen-2-ylsulf anyl) -
pyrimidin-4-yl] -amine (IIIa-8) : Prepared in a manner
STjbstantially similar to the method describe above for

20 compound IIIb-7 to afford a white solid, mp 113-115 ^C;
NMR (DMSO) S 0.35-0.91 (4H, 4xm) , 1.31 and 1.78 (IH,
2xm), 2.17 and 2.19 (3H, 2xs) ,. 2 .29 (4H, m) , 3.35 (2H, .
m) , 3.61 (2K, m), 5.38-6.20 (2K, br m) , 7.55-7.66 (3H,
m) , 7.95-8.02 (3H, m) , 8.17 and 8.23 (IH, 2xs) , 9.26 and

25 9.32 (IH, 2xbr s) , 11.71 and 11.85 (IH, 2xbr s) ; IR
(solid); MS 458.3 (M+H)*

Example 193 [6- (2 , 6-Dimethylphenyl) -2 - (naphthalen-2 -
ylsulfanyl) -pyrimidin-4-yll - (5-methyl-2H-pyrazol-3-yl) -
30 amine (Illa-9) : Prepared in a manner similar to the above
described Method L to afford an off-white solid, mp 148-
152«»C; ^H NMR (DMSO) 6 2.10 (6H, s) , 2.26 (3H, d) , 5.09
and 6.31 (IH, 2x br S), 7.03 (3H, S), 7.22 (IH, s), 7.59

-291-

(2H, t) , 7.69 (IH, d>, 7.99 (3H, d) , 8.28 (IH, s), 9.93
(IH, s), 11.67 (IH, br s) ; IR (solid) 2970, 1739, 1436,
1365^, 1229, 1217, 1205; MS 438.3(M+H)*

5 Example 194 [6- (2-Methylpheiiyl) -2- (naphtlialen-2-

ylsTil£anyl) -pyriinidin-4-yl] - (5-niethyl-2H-pyrazol-3-yl) -
amine (XIIa-10) : Prepared in a manner similar to the
above described Method L to afford a white solid, tnp 211-
2140C; NMR (DMSO) 5 1.41 (3H, s) , 2.30 (3H, s) , 5.26
10 and 6.55 (IH, 2x br s)-, 7.34 (5H, m) , 7.62 (2H, t) , 7.70

(IH, d) , 7.99 (3R, t) , 8.30 (IH, s) , 9.97 (IH, s) , 11.73 '--^
(IH, br s) ; IR (solid) 2356, 1615, 1582, 1483, 1265, 851,
822, 761; MS 424 . 0 (M+H) *

15 Example 195 [2- (4-Acetamido-phenylsulf anyl) -6-phenyl-

pyrimidin-4-yll - (5-methyl-2H-pyrazol-3-yl) -amine (ma-
il) : Prepared in a manner similar to the above described
Method L to afford a white solid, mp 153-155«»C; NMR
(DMSd) 5 2.0i (3H, S), 2.08 (3H, s) , 5.43 (IH, s) , 6.96

20 (IB, br s) , 7.49-7.88 (9H, m) , 10.00 (IH, br s) , 10.23
(IH, S), 11.86 (IH, br s); MS 417.2(M+H)*

. o

Example 196 (5-Methyl-2H-pyrazol-3-yl) - [2- (naphthalen-2-
ylsulfemyl) -6-phenyl-pyrimidin-4-yl] -amine (ZZZa-12) :

25 Prepared in a manner similar to the above described

Method L to afford a white solid, mp 237-239<»C; ^H NMR
(DMSO) S 1.39 (3H, br s) , 5.12 (IH, br s) , 6.98 (IH, br
s) , 7.50 (3H, m), 7.62-7.63 (2H, m) , 7.72 (IH, d) , 7.90
(2H, m>, 8.03-8.05 (3H, m) , 8.31 (IH, s) , 10.00 (IH, s) ,

30 11.73 (IH, br S); IR (solid) ; MS 410-2 (M+H)*

Example 197 [2- (4-le6butyrylylamlno-phenylsulf anyl) -6-
phenylpyrimidia-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine

-292-

(lIIa-13) : Prepared in a maimer similar to. the above
described Method L to afford an off-white solid, nrp 201-
2(>2»C; NMR (ra^SO) 5 1.05-1.13 (6H, m) , 1.97. (3H, s) ,
2.65 (IH, m), 5.37 (IH, br s) , 6.93 (IH, br s) , 7.50-7.58
5 (5H, m) , 7.78-7.90 (4H, m) , 9.99, 10.12 and 11.84 (3H, 3
X br s) ; IR (solid) 1676, 1614, 1586, 1573, 1514, 1483,
1395, 1299, 1262, 1242, 1214, 1168, 1089, 988; MS
445.3 (M+H)*

10 Example 198 [6- (4-Methylpiperazin-l-yl) -2-meth.ylsulf anyl-
pyriiaidin-4-yli - (5-inethyl-2H-pyrazol-3-yl) -amine (llla-
14): Prepared in a manner similar to the above described
Method M to afford an off-white solid; NMR (DMSO) 6
2.18 (3H, s) , 2.20 (3H, s) , 2.36 (4H, m) , 2.41 (3H, s) ,

15 3.46 (4H, m), 5.91 (IH, s) , 6.41 (IH, br s) , 9.20 (IH,
s), 11.87 (IH, S) ; IR (solid); MS 320.3(M+H)*

Example 199 (5-Methyl-2H-pyrazol-3-yl) - [6-phenyl-2- (4-
pre^ionylaiaino-ph.enylsulfanyl) -pyriinidin-4-yl] -amine

20 (IZXa-15) : Prepared in a manner similar to the above

described Method L to afford a pale pink solid, 204-
206»C; NMR (DMSO) 5 1.09-1.13 (3H, m) , 2.00 (3H, s) ,
2.33-2.37 (2H, m) , 5.40 (IH, br s) , 6.95 (IH, br s) , 7.50
(3H, m), 7.56-7.58 (2H, m) , 7.76-7.78 (2H, m) , 7.88 (2H,

25 m) , 9.99, 10.15 and 11.85 (3H, 3 x br s) ; IR (solid)
1678, 1623, 1580, 1534, 1496, 1453, 1398, 1307, 1245,
1203, 1119, 1049, 1030, 1004; MS 431.2 (M+H)*

Example 200 [2- (4-Cyclopropanecarbonylamino-
30 phenylsulfanyl) -6-phenylpyrimidin-4-yl] - (5-methyl-2H-
pyrazol-3-yl) -amine (XIIa-16) : Prepared in a manner
similar to the above described Method L to afford an off-

-293-

white solid, mp 253-255«»C; NMR (DMSO) 8 0.82-0.83 (4H,
m), 1.83 (IH, m) , 2.00 (3H, s) , 5.41 (IH, br s) , 6.88
(IH, br s) , 7.42-7.50 (3H, m) , 7.56-7.58 (2H, m) , 7-76-
T.78 (2H, m) , 7.89 (2H, m) , 9.99, 10.47 and 11.85 (3H, 3
X br s) ; IR (solid) 1672, 1621, 1591, 1581, 1573, 1537,
1495, 1448,. 1405, 1390, 1312, 1254, 1246i 1202, 1192,
1179, 1119. 2 > 1005, 959; MS 443.2 (M+H)*

Example 201 (5-Methyl-2H-pyrazol-3-yl) -{6-phenyl-2- [4-
(propane-l-s-ulfonylamino) -phenyl sulfanyll -pyrimldin-4-
yl}-amine (Ilia- 17) : Prepared in a manner similar to the
above described Method L to afford an off-white solid, vap
232-2350C; NMR (DMSO) 8 0.94 (3H, t) , 1.71 (2H, m) ,
2.12 (3H,s), 3.13 (2H, t) , 5.59 (IH, s) , 7.31 (2H, d) ,
7.49 (3H, s) , 7.59 (2H, d) , 7.85 (2H, s) , 10.00 (IH, br
s), 10.16 (IH, s), 12.05 (IH, br s) ; IR (solid) 1628,
1587, 1545, 1525, 1496, 1455, 1311, 1255, 1236, 1212,
1186, 1140, 1032, 1001, 934; MS 481.2 (M+H)*

Example 202 [2- (4-Stlianesulf onylaittino-phenylsulfanyl) -6-
plienyl-pyrimidin-4-yll - (5-meth.yl-2H-pyrMol-3-yl) -amine
(IXIa-18) : Prepared in a manner similar to the above
described Method L to afford a pale yellow solid> Tap 251-
254»C; *H NMR (DMSO) 8 1.21 (3H, t) , 2.12 (3H,s), 3.15
(2H, q), 5.59 (IH, s) , 7.32 (2H, d) , 7.49 (3H, s) , 7.57
(2H, d) , 7.85 (2H, S) , 9.99 (IH, br s) , 10.15 (IH, br s) ,
11.90 (IH, br s) ; IR (solid) 1621, 1585, 1542, 1523,
1495, 1455, 1315, 1257, 1208, 1142, 1049, 1033, 1002,
932; MS 467.2 (M+H)*

Example 203 [2 - ( 4 -Acetamidophenyl - sul f anyl ) - 6 - ( 2 -
methyiphenyl) -pyriiiiidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -

-294-

amine (lila-19) : Prepared in a manner similar to the
above described Method L to afford a white solid, mp 212-
214«'C; NMR (DMSO) 5 2.01 (3H, s) , 2.08 (3H, s) , 2.24
(3H, s), 5.43 (IH, S), 6.56 (IH, br s) , 7.49-7.88 (9H,
5 m) , 10.00 (IH, brs), 10.23 (IH; s) , 11.86 (IH, br s) ; IR
(solidl701, 1634, 1588, 1555, 14S6, 1390, 1307, 1208,
1169, 8^3, 803; MS 431.4 (M+H)*

Example 204 [2- (4-Isobutanecarbonylamino-phenyl-
10 sulfanyl) -6-phenyl-pyrimidin-4-yl3 - (5-methyl-2H-pyz'azol-
3-yl) -amine (IIla-20) : Prepared in a maimer similar to
the above described Method L to afford an off-white
solid, mp 241-2430C; NMR (DMSO) 8 0.95-0.96 (6H, m) ,
2.00 (3H, s) , 2.11 (IH, m) , 2.23-2.25 (2H, m) , 5.43 (IH,
15 br S), 6.95 (IH, br s) , 7.50-7.58 (5H, m) , 7.77-7.89 (4H,
m) , 10.00, 10.13 and 11.84 (3H, 3 x br s) ; IR (solid)
1660, 1628, 1589i 1575, 1543, 1525, 1496, 1451, 1398,
1357, 1314, 1301, 1251, 1206, 1108, 995; MS 459.2 (M+H) *

20 Example 205 [2- (4-Acetamido-plienyl-sulf anyl) -5-methyl-6-
plienyl-pyrlmidia-4-yl] - (5-metliyl-2H-pyra2ol-3-yl) -amine
(llIa-21) : Prepared in a manner similar to the above
described Method L to afford a pale pink solid, xtip 276-
277«>C; =^H NMR (DMSO) 5 1.98 (3H, s) , 2.08 (6H, s) , 5.41

25 (IH, br S), 7.47-7.55 (7H, m) , 7.72-7.74 (2H, m) , 8.89,
10.20 and 11.87 (3H, 3 x br s) ; IR (solid) 1676, 1591,
1555, 1540, 1519^, 1493, 1393, 1375, 1303, 1260, 1230,
1176, 1148, 1045, 1011, 969; MS 431.2 (M+H)*

30 Example 206 [2- (4-Acetamido-phenyl-sulfanyl) -6- (4-

methoxyphenyl) -pyrimidin-4-yl] - (5 -methyl -2H-pyra2ol-3-
yl) -amine (IIIa-22) : Prepared in a memner similar to the

-295-

above described Method L to afford an off white solid, mp
241-245»C; *H NMR (DMSO) 6 1.99 (3H,s), 2.06 (3H, s) , 3 .82

S). 5.44 (IH, S), 7.03 (2H, d) , 7.53 (2H, d), 7.71
(2H, S), 7.83 (2H, s) , 10.12 (IH, s) , 10.23 (IH, s) ,
5 11.84 (IH, s) ; IR (solid) 1627, 1606, 1571, 1511, 1313,
1257, 1181, 830; MS 447.2 (M+H)*

Example 207 [6- O-Acetamidophenyl) - 2- (4-acetamido-
phenyl-sulf anyl) -pyi:imidin-4-yl] - {5-methyl-2H-pyrazol-3-

10 yl) -amine (IXIa-23) : Prepared in a manner similar to the
above described Method L to afford a brown solid, mp 227-
230°C; *H NMR (DMSO) 5 2.01 (3H, s) , 2.11 (6H, s) , 5.34
(IH, S), 6.99 (IH, brs), 7.41 (IH, t), 7.49-7.62 (3H,
mV, 3.71-3.76 (3H, m) , 8.19 (IH s) , 10.09-10.18 (2H, br

15 s) , ia.23 (IH, s) , 12.20 (IH, br s) ; IR (solid) 1635,
1573, 1533, 1488, 1372, 1318, 1297, 827, 798; MS 474.3
(M+H>*

Example 208 [2- (4-lsopropanesulf onylamino-phenyl-
20 sulf anyl) -6-phenyl-pyriiiiidin-4-yl] - ( 5 -methyl -2H-pyrazol-
3-yl) -amine (XIIa-24) : Prepsured in a manner similar to
the above described Method L to afford a white solid, mp
255-2570C; ^H NMR (DMSO) 5 1.28 (6H, d) , 2.14 (3H,s), 3.32
(IH, S), 5.60 (IH, S), 7.36 (2H, d) , 7.49 (3H, s) , 7.60
25 (2H, d) , 7.85 (2H, s) , 10.00 (IH, br s) , 10.11 (IH, s) ,
11.92 (IH, br s); IR (solid) 1625, 1587) 1574, 1545,
1525, 1495, 1313,. 1295, 1257, 1234, 1136, 1000, 934; MS
481.2 (M+H)*

30 Example 209 {2- [4- (2-Dimethylamino-acetylamino) -

phenylsulf anyl] -6-phenyl-pyrimidin-4-yl}- (5-methyl-2H■-
pyrazol-3-yl) -amine (lIIa-25) : Prepared in a manner

-296-

similar to the above described Method L to afford an off-
white solid, mp 213-215«»C; *H NMR (DMSO) 6 2.00 (3H, s) ,
2.31 {6H, S) , .3.15 (2H, s) , 5.45 (IH, s) , 6.83 (IH, br
S) , 7.46-7.51 (3H, m) , 7.59 (2H, d) , 7.80-7.92 (5H, m) ,
9.98 (IH, S), 10.05 (IH, s) ; IR (solid) 1701, 1617, 1587,
1571, 1509, 1480, 1456, 1304, 1284, 1254, 1238, 1213,
1181, 1156, 987, 833, 782, 754, 695; MS 460.3 (M+H)*

Examplfe 210 [2- O-Chloro-benzylsulfanyl) -6-morpliol±n-4-
yl-pyximidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine

(IIIa-26) : Prepared in a manner similar to the above
described Method M to afford a white solid, mp 224-225«>C;
NMR (DMSa) 5 2.17 {3H, s) , 3.40-3.50 (4H, m) , 3.60-3.71

{4R, m), 4.30 (2H, s), 5.95 (IH, brs) , 6.41 (IH, brs) ,
7.23-7.55 {4H, m) , 9.31 (IH, s) , 11.89 (IH, brs); IR

(solid) 1557, 1476, 1442, 1401, 1314, 1232, 1121, 1018;
MS 417.4 (M+H)*

Example 211 12- (3-Chloro-benzylsulfanyl) -6- {2-methoxyr
ethylamino) -pyrimidin-4-yll - (5-methyl-2H-pyrazol-3-yl) -
amine (lIla-27) : Prepared in a manner similar to the
above described Method M to afford a white solid, lOl-
102«»C; NMR (DMSO) 5 2.15 (3H, s) , 3.21 (3H, s) , 3.28-
3.41 (4H, m), 4.29 {2H, s) , 5.78 (IH, brs), 6.20 (IH,
brs), 7.10 (IH, brs), 7.21-7.50 (4H, m) , 9. 01 (IH, brs);
IR (solid) 1598, 1555, 1527, 1336, 1293, 1117, 1079, 974,
783; MS 405.4 (M+H)*

Example 212 [2-Benzylsulf anyl-6- (4-methylpiperazin-l-yl) -
pyrijaidin-4-yl] - (5-inethyl-2H-pyrazol-3-yl) -amine
(lIIa-28) : Prepared in a manner similar to the above
described Method M to afford a yellow gum; ^H NMR (CDCI3)

-297-

S 2.23 (3H, s) , 2-28 (3H, s) , 2.31-2.64 (4H, m) , 3.30-
3.65 (4H, tn) , 4.38 {2H, s) , 5.83 (IH, s> , 6.23 (IH, br
s> , 7.17-7.49 (5H, m> , 7.98-8.18 (IH, m) ; IR (solid)
1555, 1494, 1371, 1315, 1286, 1233, 999, 977, 801, 774,
5 70&; MS 39^6.4 (M+H) *

Example 213 [2-Benzylsulf anyl-6-morpholiii-4-yl-pyrinii<iin-
4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIIa-29) :
Prepared in a manner similar to the above described
10 Method M to afford atn off-white foam; NMR (CDCI3) 6

2.31 {3H, S), 3.39-3.80 (8H, m) , 4.39 (2H, s) , 5.84 (IH,
s>, 6.25 (IH, brs), 7.20-7.50 (5H, m) , 8.10 (IH, s) ; IR
(solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767,
698; MS 383.4 (M+H)*

15

Exami>le 214 [2- (3-cailoro-benzylsulfanyl) -6- (4-
methylpiperazin-l-yl) -pyr.imidin-4-yl] - (5-methyl-2H-
pyrazol-3-yl) -amine. (IIIa-30) : Prepared in a manner
similar to the above described Method M to afford a white
20 foam; ^H NMR (CDCI3) 5 2.31 (3H, s) , 2.35 (3H, s) , 2,40-

2.51 (4H, m) , 3.56-3.69 (4H, m) , 4.34 (2H, s) , 5.85 (IH, ,^
s), 6.29 (IH, brs), 6.89 (IH, s) , 7.18-7.50 (4H, m) ; IR
(solid) 1553, 1514, 1484, 1446, 1277, 1228, 999, 799; MS
430.4 (M+H)*

25

Example 215 [2- (4-methoxy-benzylsulfanyl) -6- (4-
methylpiperazin-l-yl) -pyrimidin-4-yl] - (5-methyl-2H-
pyrazol-3-yl) -amine (IIIa-31) : Prepared in a manner
similar to the above described Method M to afford a
30 yellow oil; *H NMR (CDCI3) 5 2.28 (3H, s) , 2.33 (3H, s) ,
2.44-2.45 (4H, m), 3.62 (4H, .m), 3.80 (3H, s) , 4.34 (2H,
S), 5.32 (IH, s), 6.28 (IH, brs), 6.83-6.85 (2 H, m) , .

-298-

7.34-7.36 {2H, m) ; IR (solid) 1659, 1554, 1508, 1485,
1449, 1366, 1318, 1302, 1277,. 1230, 1166, 1146, 1030,
999, 973 , 948; MS 443.4 (M+H) *

5 Example 216 [2- (4-AcetaiBido-phenyl-sulfanyl) -6- tert-
butyl-pyrimidin-4-yl] - {5-jnethyl-2H-pyrazol-3-yl) -amine
(Ilia- 32) : Prepared in a manner similar to the above
described Method L to afford a white solid, mp 227-228«»C;
NMR (DMSO) 5 1.10 (3H, br s) , 1.20 (9H, s) , 2.00 -(3H,
10 s) , 2.35 (2H, q), 5.35 (IH, br s) , 6.55 (IH, br s) , 7.55
(2H, d) , 7.75 (2H, d) , 10.1 (IH, br s) , 1.15 (IH, s) ,
12.1 (IH, br s) ; IR (solid); MS (M+H) *

Example 217 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-phenyl-2-
15 ( 4 -propionylamino -phenyl -sulfanyl) -pyrimidin-4-yl] -amine
(ZXIa-33) : Prepared in a manner similar to the above
described Method L to afford an off-white solid, mp 208-
209»C; ^H NMR (DMSO) 5 0 . 52 (2H, m) , 0.80 (2H, m) . 1.08-
1.10 (3H, m), 1.65 (IH, br s) , 2.33-2.37 (2H, m) , 5.50
20 (IH, br s), 7.03 (IH, br s) , 7.47 (3H, m) , 7.50-7.58 (2H,
m), 7.76-7.77 (2H, m) , 7.88-7.98 (2H, m) , 10.00, 10.11
and 11.86 (3H, 3 X br s) ; IR (solid) 1676, 1617, 1575,
1539, 1520, 1485, 1459, 1418, 1395, 1304, 1255, 1243,
1215, 1161, 1071, 990; MS 457.4 (M+H)*
25 '

Example 218 [2- (3-Chloro-benzylsulf anyl) -6- (piperidin-1-
yl) -E^imidin-4-yl] - (5-inethyl-2H-pyrazol-3-yl) -amine
(lIIa-34) : Prepared in a msuiner similar to the above
described Method M to afford a white solid, mp 234-235'»C;
30 ^H NMR (DMSO) 6 1.40-1.64 (6H, m) , 2.13 (3H, s) , 3.42-3.51
(4H, m), 4.27 (2H, s) , 5.85 (IH, br s) , 6.46 (IH, brs) ,
7.23-7.41 (3H, m), 7.48 (IH, s), 9.18 (IH, s) , 11.83 (IH,

s) ; IR (solid) 1598, 1546, 1483, 1398, 1317, 1227, 974,
798, 779; MS 415.4 (M+H)*

Example 219 (5-Metlxyl-2H-pyrazol-3-yl) -{2- [4-
5 (morpholinesulfonyl) -benzylsulfeuiyl] -6-iiiorpholin-4-yl-
pyriiaidin-4-yl}-amine (IIIa-35) : Prepared in a manner
similar to the above described Method M to afford a white
solid; NMR (DMSO) 5 2.24 (3H, s) , 2.90-3.01 (4H, m) ,
3. 29-3-. 36 (4H, m) , 3.48-3.57 (4H, m) , 3.67-3.75 (4H, m) ,
10. 4.43 {2K, S), 5.82-6.10 (2H, m) , 7.50-7.70 (5H, m) ; IR
(solid) 1550, 1483, 1441, 1346, 1308, 1255, 1160, 1112,
941, 726; MS 532.5 (M+H).*

Example 220 {6- (2-Methoxy-etliylaiBino) -2- [4-
15 (morpliolinesulfemyl) -benzylsulfanyl] -pyrimidin-4-yl}- (5-
metliyl-2H-pyrazol-3-yl) -amine (IIIa-36) : Prepared in a
manner similar to the above described Method M to afford
a white solid, rap 193-1950C; *H NMR (DMSO) 6 2.15 (3H, s) ,
2.79-2.89^ (4H, m) , 3.34 (3H, s) , 3.40-3.51 (4H, m) , 3.59-
20 3.67 (4H, m), 4.41 (2H/ s) , 5.76-5.72 (IH, m) , 6.20 (IH,
brs), 7.10 (IH, brs) , 7.61-7.74 (4H, m), 9.03 (IH, brs),
11.81 (IH, brs); IR tsolid) 1593, 1555, 1484, 1350, 1298,
1255, 1160, 1107, 936; MS 520.5 (M+H) *

25 Example 221 {6- (4-methylpiperazin-l-yl) -2-^ [4-

(morphblinesulfonyl) -benzylsulfanyl] -pyrimidin-4-yl}- (5-
niethyl-2H-pyrazol-3-yl) -amine (Illa-37) : Prepared in a
manner similar to the above described Method M to afford
a white solid, mp 206-207OC; NMR (DMSO) 5 2.09 (3H, s) ,

30 2.20 (3H, s) , 2.26-2.40 (4H, m) , 2.78-2.88 (4H, m) , 3.38-
3.49 (4H, m) , 3-. 56-3. 67 (4H, m) , 4.41 (2H, s) , 5.82 (IH,
brs), 6.42 (IH, brs), 7.60-7.74 (4H, m), 9.26 (IH, s) , .

-300-

11.89 (IH, l>rs) ; IR (solid) 1583, 1558, 1479, 1346, 1231,
116a, 1112, 998, 969, 926; MS 545.5 (M+H)*

Example 222 [ 6 -Methoxymethyl -2 - (4 -propionylamino -phenyl -
sulfanyl) -pyrim±d±n-4-yl] - (5-iaethyl-2H-pyrazol-3-yl) -
amine (IXXa-38) : Prepared in a mamier similar to the
above described Method L to afford a white solid; NMR
(DMSO) 5 1.03-1.14 (3H, m) , 2.00 (3H, s) , 2.29-2.40 (2H,
m) , OMe imder DMSO, 4.22 (2H, m) , 5.26 (IH, brs) , 6.45
(IH, brs), 7.44-7.56 (2H, m) , 7.68-7.80 (2H, m) , 9.86
(IH, brs), 10.11 (IH, s) , 11.79 (IH, brs); IR (solid)
1670, 1593, 1517, 1479, 1393, 1360, 1269, 1174, 1107; MS
399.4 (M+H)*

15 Example 223 [2- (4-Methoxycarbonyl-phenyl-sulf anyl) -6-

methoxymethyl-pyrimidin-4-yl] - (5-inethyl-2H-pyrazol-3-yl) -
amine (IIIa-39) : Prepared in a manner similar to the
above described Method L to afford a white solid, mp 204-
205«C; NMR (DMSOy 5 1.89 (3H, brs), 3.85 (3H, s) , OMe

20 under DMSO, 4.23 (2H, s) , 5.22 (IH, brs), 6.51 (IH, brs),
7.70-7.81 (2H, m) , 7.96-8.06 (2H, m) , 9.99 (IH, brs),
11.85 (IH, brs); IR (solid) 1721, 1621, 1583, 1519, 1484,
1289, 1271, 1178, 1119, 1109, 997, 841; MS 386.3 (M+H)*

25 Exanqple 224 [2- (3,5-Dimethoxy-benzylsulf anyl) -6-

morpholin-4-yl-pyrimidin-4-yl] - (5 -methyl- 2H-pyra2ol-3-
yl) -amine (IIIa-40) : Prepared in a manner similar to the
above described Method M to afford a white solid; ^H NMR
(DMSO) 6 2.15 (3H, s)., 3.40-3.49 (4H, m) , 3.60-3.74 (lOH,
30 m), 4.25 (2H, s) , 5.88 (IH, brs), 6.31-6.61 (5H, m) , 9.32
. (IH, s) , 11.86 (IH, s) ; IR (solid) 1581, 1556, 1470,
1439, 1315, 1232, 1205, 1159, 1144; MS 443.4 (M+H) *

10

-301-

Exanvple 225 . 12- (3 , 5-Dlmethoxy-benzylsulf anyl) - 6-
pyrrolidin-4-yl-pyriniidizi-4-yll - (5-meth.yl-2H-pyrazol-3-
yl) -amine (lIIa-41) : Prepared in a manner similar to the
5 above described Method M to afford a white solid; ^ NMR
(DMSO) 5 1.80-1.97 (4H, m) , 2.15 {3H, s) , 3.43-3.45 (4H,
m) , 3.69 (6H, S) , 4.26 (2H, s) , 5.85 (IH, brs) , 6.18 (IH,
brs), 6.35 (IH, brs) , 6.60 {2H, s> , 9.12 (IH, s) , 11.88
(IH, s) ; IR (solidl598, 1560, 1474, 1470, 1346, 1303,
10 1207, 1136, 1050; MS 427.4 (M+H) *

Example 226 (5-Methyl-2H-pyrazol-3-yl) - C6-morpholin-4-yl-
2- (naphthalene -2 -ylmethylsulf anyl) -pyrimidin-4-yl] -amine
(IIla-42) : Prepared in a manner similar to the above

15 described Method M to afford an off-white solid; ^H NMR
(DMSO) 5 2.15 (3H, s) , 3.37-3.50 (4H, m) , 3.59-3.70 (4H,
m), 4.48 (2H, s) , 5.88 (IK, brs), 6.40 (IH, brs), 7.40-
7.60 (3H, m), 7.78-7.95 (4H, m) , 9.30 (IH, s) , 11.89 (IH,
brs); IR (solid) 1607, 1555, 1484, 1441, 1398, 1365,

20 1308, 1231, 1179, 1112; MS 433.4 (M+H)*

Example 227 {2- (4-AGetamido-phenyl-sttlfanyl) -6- [4- (3-
diaathylaiaino-propoxy) -phenyl] -pyrimidin-4-yl}- (5-methyl-
2H-pyrazol-3-yl)-amine (XIZa-43) : Prepared in a manner

25 similar to the above described Method N to afford a white
solid, rap 21&-222*C; *H NMR {CDCI3) 5.1.97-2.07 (2H, m) ,
2.14 (3H, s) , 2.18 (3H, s) , 2.30 (6H, s), 2.52 (2H, t) ,
4.09 (2H, t) , 5.56 (IH, s) , 6.80 (IH, brs), 6.99 (2H,
d) , 7.60 (2H, d) , 7.68-7.78 (3H, m) , 7.85 (2H, d) ; IR

30 (solid) 1606, 1590, 1512, 1482, 1309, 1250, 1238, 1210,
1178, 1151, 1055, 989, 824, 711, 690, 665, 656; MS 518.4
(M+H)*

-302-

Example 228 [2- (4-Acetamidophenylsulf anyl) -6- (morpholin-
4-yl) -pyrimidin-4-yl] - ( 5 -methyl -2H-pyrazol- 3 -yl) -amine
(XIZa-44) : Prepared in a manner similar to the above
5 described Method P to -afford a white solid; MS 426.4
(M+K)*

Example 229 [6 -Hydroxymethyl - 2 - ( 4 -propionylamino-phenyl-
sulfanyl) -pyrimidia-4-yll - (5-methyl-2H-pyrasol-3-yl) -

10 amine (IIIa-45) : Prepared from IIIa-48 according to

Method O to afford a white solid; NMR (DMSO) 5 1.08-
1.18 (3H, m) , 1.96 (3H, brs) , 2.29-2.40 (2H, m) , 4.20-
4.40 (3H, m), 5.20-5.46 (2H, m) , 6.56 (IH, s) , 7.50 (2H,
d) , 7.79 (2H, d) , 9.90 (IH, brs) , 10.13 (IH, s) , 11.78

15 (IH, brs) ; MS- 385 .4 (M+H) *

Example 230 [2- ( 4 -Acetamido -phenyl -sulf anyl) -pyrimidin-4-
yl] - (5 -methyl- 2H-pyrazol-3-yl) -amine (IIZa-46) : Prepared
in a manner similar to the above described Method L to

20 afford an off-white solid, mp 249-250OC; NMR (DMSO) 8.

1.99 (3H, s), 2.08 (3H, s), 5.38 (IH, br s) , 6.45 (IH, br .
s) , 7.50 (2H, d) , 7.71 (2H, d) , 7.98 (IH, d), 9.89 (IH,
br s), 10.19 (IH, br s) , 11.83 (IH, br s) ; IR (solid)
1657, 1609, 1584, 1515, 1494, 1468*, 1395* 1372, 1355,

25 1330, 1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M+H)*

Example 231 16- { 1 -Butoxyceurbonyl ) - 2 - ( 4 -propionylamino-
phenyl-sulf anyl) -pyriinidin-4-yl] - (5-methyl-2H-pyrazol-3-
yl) -amine (ZZIa-47) : Prepared in a manner similar to the
30 above described Method L to afford a yellow solid, ^H NMR
(DMSa) 5 0.90-0.98 (3H, m) , 1.03-1.12 (3H, m) , 1.31-1.45
(2H, m), 1.60-1.71 (2H, m), 1.94 (3H, brs) , 2 . 29-2 . 40

-303-

(2H, m) , 4.20-4.30 (2H, m) , 5.25 (IH, brs) , 7.08 (IH,
brs), 7.49-7.55 (2H, m) , 7.72-7.81 (2H, m) , 10.15 (IH,
brs), 10.32 (IH, br&) , 11.89 (IH, brs) ; IR (solid) 1736,
1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 (M+H) *
5 ...

Example 232 [ 6 -Methoacycarbonyl - 2 - ( 4 -propionylamino-
phenyl - sul f anyl ) -pyr imidln- 4 -yl ] - ( 5 -methyl - 2jff-pyra2ol - 3 -
yl) -amine (IIla-48) : Prepared in a manner similar to the
above described Method L to afford a yellow solid; NMR
10 (DMSO) 5 1.10 (3H, t) , 1.94 (3H, brs) , 2.35 (2H, q) , 3 . 84
(3H, S) , 5.22 (IH, brs), 7.05 (IH, s) , 7.52 (2H, d) , 7.79
(2H, d) , 10.18 (IH, brs), 10.38 (IH, brs), 11.89 (IH,
brs).; IR (solid) 1741, 1679, 1617, 1589, 1512, 1484,
1374, 1284, 1250; MS 413.4 (M+H)*

15

Example 233 (5-Methyl-2H-pyrazol-3-yl) - (6-phenyl-2-
phenylaiaino-pyriinidin-4-yl) -amine (IIlc-1) : white . solid;
MS 343.4 (M+H)*

20 Example 234 (5-Cyclopropyl-2H-pyrazol-3-yl) - (6-phenyl-2-
phenylamino-pyrimidin-4-yl) -amine (IIIc-2) : white solid,
mp 267-269<»C; NMR (DMSO> 6 0.63 (2H, m) , 0.96 (2H, m) , Q
1.87 (lK,m) , 6.07 (IH, s) , 6-84 (IH, br s) , 7.20 (IH, m) ,
7.33-8. OS (9H, m) , 10.52 (IH, br s) , 11.08 (IH, br s) ,

2S 12.53 (IH, br S); IR (solid); MS 369.7 (M+H)*

Example 235 (5-Cyclopropyl-2H-pyrazol-3-yl) - 12- (3-
methylphenylamino) -6-phenyl-pyrimidin-4-yl] -amine (Illc-

3) : White solid, rap 267-270«»C; *H NMR (DMSO) 5 0.63 (2H,
30 m), 0.94 (2H, m) , 1.87 (lH,m) , 2.36 {3H, s) , 6.12 (IH,
s), 6.81 (IH, br s), 7.03 (IH, m), 7.29-7.94 (8H, m) ,
10.43 (IH, bf S), 11.12^ (IH, br s) , 12.47 (IH, br s) ; IR
(solid) ; MS 383.7 (M+H)*

-304-

Example 236 [2 - { 4 - cyanome thylphenylamino) - 6 -phenyl -
pyriiaidin-4-ylJ - (5-cycloprbpyl-2H-pyrazol-3 -yl) -amine
(IIIc-4) : pale yellow solid, mp 294-297»C; NMR (DMSO) 5
0.64 (2H, m) , 0.97 (2H, m) , 1.89 (IH, m) , 4.06 (2H, s) ,
6.07 (IH, s) , 6.87 (IH, br s) , 7.40 (2H, m) , 7.63-7,90
{5», m)/ 7.95 (2H, m), 10.51 (IH, br s) . 11.02 (IH, br
s), 12.57 (IH, br s) ; IR (solid); MS 408-8 (M+H)*

Example 237 (5-Cyclopropyl-2H-pyrazol-3-yl) - [6-phenyl-2-
(pyridin-3-yliaethylamino) -pyriinidin-4-yl] -amine (IIlc-5) :
Off-wbite solid, mp 191-193-C; NMR (DMSO) 8 0.65 (2H,
m), 0.89 {2H, m), 1.83 (IH, m) , 4.59 (2H, s) , 6.04 (IH,
br s), 6.76 (IH, br s) , 7.32-7.56 (5H, m) , 7.77 (IH, m) ,
7.88-7.&7 (2H, m) , 8.43 (IH, m) , 8161 (IH, s) , 9.47 (IH,
br s), 11.93 (IH, br s); IR (solid); MS 384.8 (M+H)*

Example 238 [2- (3 -Chlorophenyl) amino-6- (3 -nitrophenyl) -
pyrimidin-4-yl3 - (5-metliyl-2H-pyrazol-3-yl) -amine (IIIc-
6): off-white solid; ^H NMR (CD3OD) 5 5.95 (IH, s) , 6.65
(IH, s), 6.90 (IH, dy. 7.18 (IH, t) , 7.32 (IH, d) , 7.58
(IH, t), 7.82 (IH, S), 8.18 (IH, d) , 8.25 (IH, d) , 8.65
(IH, s) ; MS 422.1 (M+H)*

Example 239 [2- (3-cailorophenyl)amino-6- (3,4,5-
trlmethoxyphenyl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-
yl) -amine (lIIc-7) : white solid; MS 467.7 (M+H)*

Example 240 (5-Methyl-2H-pyrazol-3-yl) - E2- (4-
sulfamoylphenylamino) -6- (3,4,5-trimethoacyphenyl) -
pyrimidin-4-yl] -amine (IlIc-8) : white solid,: ms 512.6
(M+H)*

-305-

Example 241 [2- (4-Chlorophenyl) aaaino- 6 -methyl -pyrimidin-
4-yl] - [5- (furan-2-yl) -2H-pyrazol-3-yl] -amine (IlIc-9) :
white solid; MS 367.1 (M+Hh*

5 Example 242 [2- (Benzimidazol-2-ylamino-) 6-etlxyl-

pyrimidixi-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (lllc-
10) : MS 335.5 (M+H)*

Example 243 [2- (4-C!hlorophenyl) amino- 6 -methyl -pyrl m idi n -
10 4-yl] - (5-phenyl-2JI-pyrazol-3-yl) -amine (IIlc-11) : MS
377.5 (M+H)*

Example 244 [2 - ( 4 -Chlorophenyl ) amino- 6 - ethyl -pyrimidin- 4
yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIZc-12) : MS 329.4

15 (M+»>*

Example 245 (5- tert-Butyl-2H-pyrazol-3-yl) - [2- (3-
chlorophenyl) amino-6- (3-nitrophenyl) -pyrimidin -4-yl] -
amine (IIIc-13) : off-white solid; NMR (CD3OD) 6 1.32
20 (9H, s) , 6.18 (IH, s) , 7.04 (IH, s), 7.14 (1H, d) , 7.35
(IH, t) , 7.58 (IH, d), 7.82 (IH, t) , 7.91 (IH, s) , 8.35
(IH, d) , 8.40 (IH, d), 8.9a (IH, s) ; MS 464.2 (M+H)*

Example 246 [2- (3 -Chlorophenyl) amino-6- (3-nitrophenyl) -
25 pyrimidin- 4-yl] - (5-phenyl-2H-pyrazol-3-yl) -amine

(XZIc-14) : 5 off-white solid; ^H NMR (CD3OD) 6 6.66 (IH,
s) , 7.12 (IH, d) , 7.30-7.45 (5H, m) , 7.50 (IH, d) , 7.62

(2H, d), 7.78 (IH, t), 7.88 (IH, s) , 8.35 (IH, d) , 8.42

(IH, d) , 8.85 (IH, S); MS 484.1 (M+H)*

30

Example 247 [5- (Puran-2-yl) -2H-pyrazol-3-yl] - (6-phenyl-2
,phenyl'amino-pyrimidin-4-yl) -amine (lXZc-15) : MS 395.4

(M+H)*

-306-

Example 248 [2- (Beazimidazol-2-ylaiaino) -6-methyl-
pyrimid±n-4-yll - (5-phenyl-2H-pyrazol-3-yl) -amine (IIlc-
16) : MS 383.2 (M+H)*

Example 249 [2- (Benziiiiidazol-2-ylaiBino) -6-methyl-
pyriiaidin-4-yl] - [5- {Puran-2-yl) -2H-pyrazol-3-yl] -amine
(lllc-17) : MS 373.4 (M+H)*

Example 250 [2- (4-Chlorophenylamino) - 6 -methyl -pyrimidin-
4-yll - (5-metliyl-2H-pyrazol-3-yl) -amine (IIlc-18) : MS

31S.4 (M+H)*

Example 251 [2 - (4 -Chlorophenyl ) amino- 5 , 6 -dimethyl-
pyrimidin-4-yl] - (5-met:hyl-2H-pyrazol-3-yl) -amine (Ilic-
19) : MS 329.4 (M+H)*

Example 2^52 (5, 6-Dimetliyl-2-phenylamino-pyrimidin-4-yl)
{5-meth.yl-2>H-pyrazol-3-yl)-amine (IIIc-20) : MS 295.5
(M+H)*-

Example 253 £2 - ( 4 - Chlorophenyl ) amino - 6 -me thoxymethyl -
pyrimidin- 4-yll - (5-methyl-2H-pyrazol-3-yl) -amine (IIlc-

21) : MS 345.1 (M+H)*

Example 254 [2- (Benzimidazol-2-ylamino) -6 -me thoxymethyl
pyrimidin-4-yll - (5-methyl-2H-pyrazol-3-yl) -amine (IIIc-

22) : MS 351.2 (M+H)*

Example 255 (6-Methoxymethyl-2-phenylamino-pyrimidin-4-
yl) - (5-methyl-2H-pyrazol-3-yl) -amine (IIIc-23) : MS 311.
(M+H)*

-307-

Example 256 (6-Methyl-2-phenylaiiiino-pyrimidin-4-yl) - (5-
]aethyl-2H-pyrazol-3-yl) -amine (ZIZc-24) : MS 281.1 (M+H)^

Example 257 [2- (2-cailorc^henoxymethyl) -6-methyl-
5 pyrimidin-4-yl] - (5-phenyl-2fl'-pyrazol-3-yl) -sanine (IXZd-
1) : MS 3S2.1 (M+H)*

Example 258 [2- (2-Ch,lorophenoxymethyl) -6-methyl-
pyrimidin-4-yl] - [5- (£uran-2-yl) -2H-pyrazol-3-yl] -amine
10 (IIXd-2): MS 382.1 (M+H)*

o

Example 259 (6-iiiethyl-2-pheiioxymethyl-pyrijnidiii-4-yl) - (5-
phenyl -2H-pyrazol- 3 -yl) -amine (lIId-3) : MS 358.2 (M+H)*

15 Example 260 E5- (Puran-2-yl) -2H-pyrazol-3-yl] - (6-methyl-2-
phenoxyineth,yl-pyrixaldln-4-yl) -amine (XXId-4) : MS 348.2
(M+H) *

Example 261 [5- (Furan-2-yl) -2H-pyrazol-3-yl] - (6-methyl-2-
plIenylsul£anylmetixyl-pyrlmld±n-4-yl) -amine (lXXd-5) : MS
364.1 (M+H)*

• " ■ o

Example 262 [6-Methyl-2- (4 -methyl -phenylsulfanylmetliyl} -
pyrimldin-4-yl] - (5-phenyl-2H-pyrazol-3-yl) -emine (ZZId-
6) : MS 388.1 (M+H)*

Example 263 15- (Piiran-2-yl) -2H-pyrazol-3-yl] - t6-Methyl-2-
(4-met:hyl-phenylsulfanylmethyl) -pyrimidln-4-yl] -amine
(XZZd-7): MS 378.1 (M+H)*
30

Example 264 [2- (4-Pluoro-plieno3cymethyl) -6-methyl-
pyrimidin-4-yll - (5-phenyi-2H-pyrazol-3-yl) -amine (ZZZd-
8) : MS 376.2 (M+H)*

20

25

-308-

Example 265 12- (4-Pluoro-plienoxymethyl) -6-iaethyl-
pyrlnd.din-4-yl] - [5- (fTzran-2-yl) -2H-pyrazol-3-yl] -amine
(IIXd-9) : MS 366.2 (M+H)^*
5 •• ... -•

Example 2 66 ( 6 -Ethyl - 2 -phenylsul f anylmethyl -pyr iioidin- 4 -
yl)-(5-metliyl-2H-pyrazol-3-yl) -amine (lIId-10) : MS 326.2

(M+H)*

10 Example 267 (6-Bthyl-2^plieno3cymethyl-pyrimidin-4-yl) - (5-
metliyl-2H-pyrazol-3-yl) -amine (IIId-11) : MS 310.2 (M+H)*

Example 268 I6-Ethyl-2- (4-f luorophenoxymethyl) -pyrlmidin-
4-yll - (5-meth.yl-2H-pyrazol-3-yl) -amine (IIId-12) : MS
15 328.2 (M+H)*

Example 269 [6-Bthyl-2- (l-methyl-l-phenyl-ethyl) -
pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Illd-
1,3) : MS 322.2 (M+H)*

20

Example 270 [2- {4-cailororoplienoxymethyl) -6-methyl-
pyrimidin-4-yl] - (5-phenyl-2JI-pyrazol-3-yl) -amine (Illd-

14) : MS 392. 2 (M+H)*

2S- Example 271 [2 - ( 4 - Chlororophenoxyme thyl ) - 6 -methyl -

pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (Illd-

15) : MS 330.2 (M+H)*

Example 272 [2- (4-Chlororophenoxymethyl) -6-methoxymethyl-
30 pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) -amine (llld-

■ 16): white solid; ^H NMR (DMSO) 5 2.20 (3H, s) , 3.43 (3H,
s), 4.49 (2H, s), 5.20 (2H, s) , 6.05 (IH, br) , 7.05 (2H,
d), 7.33 (2H, d>, 10.55 (IR, br) ; MS 360.2 (M+H)*

-309-

Example 273 [2- {4-Chlororophenoxymethyl) -S-methyl-
pyrimidin-4-yll - C5- (furan-2-yl) -2H-pyrazol-3-yl] -amine
(IIId-17) : MS 3a2i2 (M+H) *

Example 274 (5-Methyl-2H-pyrazol-3-yl) - (2-
phenylsulfanylmetliyl-5, 6,7, 8-tetraliydro-quinaaolin-4-yl)

amine (IId-7) : MS 352.5 (M+H)*

Example 275 [2- {4-Metlxylphenylsulf anylmethyl) -6,7,8,9-
tetrsaiydro-5H-cyclolieptapyrimidin-4-yl] - (5-metbyl-2H-
pyrazol-3-yl) -amine (IId-8) :MS 380 . 2 (M+H)*

Example 276 [2- (l-Methyl-l-plienyl-ethyl) -6,7,8,9-
tetrah.ydro-5H-cyclolieptapyrlmidin-4-yl] - ( 5 -methyl - 2H-
pyrazol-3-yl) -amine (IId-9) :
MS 362.3 (M+H)*

Example 277 [2- (2, 6-Dichlorobe^zyl) -5, 6,7, 8-tetraliydro-
qiiinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ild-
10) t MS 388.1 (M+H)*

Example 278 t7-Benzyl-2- (2, 6-diclilorobenzyl) -5,6,7,8-
tetrahydropyrido [3 , 4-d3 pyrimidin-4-yl] - (5-meth.yl-2H-
pyrazol-3-yl) -amine (IId-11) s MS 479 . 5 (M+H)*

Example 279 [6-Benzyl-2- (4-cliloroplienoxymethyl) -5,6,7, 8-
tetrabydro-pyrido [4,3-d]pyrimidin-4-yl] - (5-methyl-2H-
pyrazol-3-yl) -amine (IXd-12) : MS 461.2 (M+H)*

Example 280 [2- (4-Chlorophenoacymethyl) -5,6,7,8-
tetrahydro-pyrido [4,3-d]pyrimidin-4-yl] - (5-methyl-2H-
pyrazol-3-yl) -amine (Ild-13) s MS 371.3 (M+H)*

-310-

Exaittple 281 t2 - (2 , 6-Dichlorobenzyl) - 6 -methyl -pyrimidin- 4 -
yll-(5-methyl-2H-pyrazol-3-yl) -amine {lIId-18) : MS 348.1

(M+H)*

5 ■

Example 282 12- (2, 6-Dichlorobenzyl) -5, 6 -dimethyl -
pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine {llld-
19): white solid; NMR (DMSO) □ 8.50 (IH, s) , 7.70 (IH,
d), 7.3-7.1 (3H, m), 5.25 (IH, s) , 4.10 (IH, s) , 2.30
10 (3H, s), 2.10 (3H, S), 1.80 (3H, s) ; MS 362.1 (M+H) *

Example 283 (lH--lndazol-3-yl) - (2- (2-phenyl-cyclopropyl) -
quinazolin-4-yl] -amine (Ild-16) : ^HNMR (DMSO) 13.2 (IH, s) ,
12.0(1H, s), 8.76(1H, m) , 8.10(1H, m) , 7.85(2H, m),
15 7.75 (IH, m) , 7.61 (IH, m) 7.41 (IH, m) . 7.30 (2H, m) ,
7.20(2H, m), 7.12(2H, m) , 2:35{2H, m) , 1.60(1H, m) ,
l.:i5(lH, m) ; MS: m/z, 378.1 MH+; HPLC Rt=3.21 tliin..

Example 284 (7-Fluoro-lH-indazol-3-yl) - [2- (2-phenyl-
20 cyclopropyl)-quinazolin-4-yl]-amine {Ild-17) : =^HNMR (DMSO)
13.8 (IH, S) , 12.05(1H, s) , 8.75 (IH, m) , 8.10 (IH, m) ,
7-.85(2H, m>, 7.6&(1H, m) , 7.35 (3H, m) 7 . 25-7 . 10 (4H, m) ,
2.35(2H, m), 1.60(1H, m) , 1.35(1H, m) ; MS: m/z, 396.1
MH+; HPLC Rt=3.26 min.

25

Example 285 (5-Pluoro-lH-indazol-3-yl) - [2- (2-phenyl-
cyclopropyl)-quinazolin-4-yl] -amine (IId-18) : ^HNMR (DMSO)
13.3(1H, S), 12.0(1H, s), 8.75(1H, m) , 8.10(1H, m) ,
7.85(2H, m), 7.65(2H, m) , 7.35 (3H, m) 7,20 (IH, m) ,
30 7.10(2H, m) 2.40 (2H, m) , 1.65(1H, m), 1.35(1H, «v); MS:
m/z, 396.1 MH+; HPLC Rt=3.26 min.

-311-

Example 286 (5-Methyl-lH-pyrazol-3-yl) - [2- (2-phenyl-
cyclopropyl)-quinazoliii-4-yl] -amine (IId-19) : ^HNMR (DMSO)
12.8 (IH, S) , 11.90 (IH, s) , 8.80 (IH, m) , 8,10 (IH, m) ,
7.8S(2H, m) , 7 • 30-7 • 20 {5H, m) , 6.55 (IH, s) 2.80 (IH, m) ,
2.55(1H, m) , 2.35 (3H,s) 2.00(2H, m) ; MS: m/z, 342.1 MH+;
HPLC Rt=3.13 min.

BIOIiOGICAIi TESTING
The activity of the compoimds as protein kinase
inhibitors may be assayed In vitror in vivo or in a cell
line. In vitro assays include assays that determine
inhibition of either the phosphorylation activity or
ATPase activity of the activated protein kinase.
Alternate in vitro assays quantitate the ability of the
inhibitor to bind to the protein kinase. Inhibitor
binding may be measured by radiolabelling the inhibitor
prior to binding, isolating the inhibitor/protein kinase
complex and deterroining the amount of radiolabel boxind.
Alternatively, inhibitor binding may be determined by
running a competition experiment where new inhibitors are
incxibated with the protein kinase bound to known
radioligands •

BIOLOGICAIi TESTING EXAMPLE 1
K j DETERMINATION FOR THE INHIBITION OF GSK-3

Compoiinds were screened for their ability to
inhibit GSK-3p (AA 1-420) activity using a standard
coupled enzyme system (Fox et al. (1998) Protein Sci. 7,
2249) . Reactions were carried out in a solution
containing 100 mM HEPES (pH 7.5), 10 uiM MgCla, 25 mM NaCl,
300 iiM NADH, 1 mM DTT and 1.5% DMSO. Final substrate
concentrations in the assay were 20 pM ATP (Sigma
Chemicals, St Louis, MQ) and 300 pM peptide

-312-

{HSSPHQS^(P03H2)EDEEE, American Peptide, Sxannyvale, CA) .
Reactions were carried out at 30 ''C and 20 nM GSK-3p.
Final concentrations of the components of the coupled
enzyme system were 2,5 mM phosphoenolpyxuvate , 300 ^M
5 NADH, 30 iig/ml pyruvate kinase and 10 ug/ml lactate
dehydrogenase.

An assay stock buffer solution was prepared
containing all of the reagents listed above with the
exception of ATP and the test compound of interest. The

10 assay stock buffer solution (175 ill) was incxibated in a
96 well plate with 5 pi of the test compoxond of interest
at final concentrations spanning 0.002 to 30 pM at 30**C
for 10 min. Typically, a 12 point titration was
conducted by preparing serial dilutions (from 10 mM

IS compound stocks) with DMSO of the test compounds in
dau^ter plates-. The reaction was initiated by the
addition of 20 of ATP (final concentration 20 viM) .
Rates of reaction were obtained using a Molecular Devices
Spectramax plate reader (Sunnyvale, CA) over 10 min at

20 30®C. The Ki values were determined from the rate data as
a function of inhibitor concentration.

The following compotonds • were shown to have Ki
values less than 0.1 jiM for GSK-3: IIa-2, IIa-3, IIa-8,
Ila-9^, IIa-11, IIa-12, IIa-17, IIa-18, IIa-21 to IIa-24,

25 IIa-26, IIa-2a, IIa-30 through II a-32, IIa-39, IIa-43,
IIa-46, IIa-47, IIa-61, IIC-3, IIC-6, IIc-8, IIC-10
through IIc-12, IIc-15, IIc-18, IIc-20 through IIc-22,
IIc-24, IIc-25, IIc-27, IIc-30 through IIC-32, IIc-35 to
IIC-39, IIc-42, IIC-53, IIc-61, IIC-67, IIc-77, IIc-78,

30 IIb-1, IIb-3, IIb-5, IIb-8, IId-1, IIIa-2, IIIa-3, Ilia-
6, IIIa-17, IIIa-18, IIIa-24, IIIa-27, IIIc-2 through
IIIc-5, IIIc-9, IIIc-11, IIIc-12, IIIc-15, IIIc-18, IIIc-

-ala-
lia, 1110-2-1, IIIc-24, Illb-l through IIIb-6, IIIb-8
through IIIb-10, IlIb-13, lIIb-14, IIId-20, llld-2l, lld-
14, and IId-l&.

The following compounds were shown to have K±

values between 0.1 and 1;0 |JM for GSK-3: IIa-1, IIa-4,
IIa-5, lIa-7, Ila-14, Ila-lS, IIa-20, Ila-29, IIa-34
through IIa-36, ila-38, IIa-41, IIa-42, IIa-48, IIa-54,
IIa-55, IIa-62, Ila-63, IIa-66, IIa-69, IIa-78, IIc-1,
IIc-2, IIc-4, IIc-5, IIc-7, IIc-9, IIc-13, IIc-14, IIc-
16, IIC-17, IIC-19, IIc-23, IIc-26, IIc-28, IIC-29, Ilc-
33, IIC-34, IIC-40, IIC-41, IIc-43 through IIC-45, IIC-47
through lie -52, IIc-54 through IIc-57, IIc-59, IIc-63
through IIC-66, IIC-72, IIc-75, IIc-76, IIc-79, IIC-6,
IIb-7, IIb-9, IId-2, IId-5, IId-6, Illa-l, IIIa-4, Illa-
5, IIIa-7, IIIa-8, IIIa-10, Illa-ll, IIIa-19, IIIa-22,
IIIa-23, IIIa-26, IIIa-29, IIIa-30, IIIa-31, IIIa-33,
IIIa-34, IIIa-37, IIIa-42, IIIc-1, IIIc-8, IIIc-20, IIIc-
23, IIIb-7, IIIb-11, IIIb-12, IIIb-15, IIIb-16, IId-16,
IId-17, and IId-18.

The following compotmds were shown to have Ki
values between 1.0 and 7.0 jiM for GSK-3: IIa-10, IIa-13,
IIa-25, IIa-40, IIa-45, lla-49, IIa-50 through IIa-52,
IIa-64, IIa-65, ila-67, IIa-68, IIa-71, iIa-72, lla-74,
IIa-76, lIa-77, IIa-81, IIc-58, IIc-SO, IIc-62, IIc-68
through IIc-71, Ilc-74, IId-3, IId-4, IIIa-15, Ilia- 16;
IIIa-21, IIIa-28, lIIa-35, IIIa-36, IIIa-38, IIIa-41,
IlIa-43, IIIa-45, IIIa-49, IIIc-10, IIIc-16, IIIc-17, and
IIIc-22 .

BIOLOGICaii TESTING EXAMPLE 2
K^ DETERMINATION FOR THE INHIBITION OF AURORA- 2

Con5)ounds were screened in the following meUiner
for their ability to inhibit Aurora- 2 using a standard

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coupled enzyme assay (Fox et al (1998) Protein Sci 7,
2249).

To an assay stock buffer solution containing

0. 1M HEPES 7.5, 10 tnM MgCla, 1 mM DTT, 25 niM NaCl, 2.5 tnM
5 phosphoenolpyruvat-e, 300 mM NADH, 30 mg/ml pyruvate

kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and
800 pM peptide (LRRASLG, American Peptide, Siinnyvale, CA)
was added a DMSO solution of a compound of the present
invention to a final concentration of 30 \M. The

10 resulting mixture was incubated at 30 'C for 10 min. The
reaction was initiated by the addition of 10 ]aL of
Aurora- 2 stock solution to give a final concentration of
70 nM in the assay. The rates of reaction were obtained
by monitoring sJasorbance at 340 nm over a 5 minute read

15 time at 30 using a BioRad Ultramark plate reader

(Hercules, CA) . The Ki values were determined from the
rate data as a function of inhibitor concentration .

The following compounds were shown to have Ki
values less than 0.1 fiM for Aurora-2: IIa-1 through Ila-

20 18, IIa-21 through IIa-64, IIa-66, IIa-68, IIa-69, IIa-71
through IIa-78, IIa-81, IIc-1 through IIc-13, IIc-15
through IIc-44, IIc-46 through IIc-61, lie- 63 through
IIc-65, IIc-67 through IIc-69, IIb-1 through IIb-9, IXd-1
through IId-3, IIIa-1 through IIIa-8, IIIa-10 through

25 lIIa-13, IIIa-15 through IIIa-32,IIIa-36 through Ilia-

41, IIIa-44 through XIIa-49, IIIc-1 through IIIc-5, IIIc-
12, and IIIc-15.

The following compounds were shown to have Ki
values between 0.1 and 1.0 JIM for Aurora-2: IIa-20, Ila-

30 65, IIa-67, Ila-70, IIa-80, IIc-14, IIc-66, IId-5, IId-6,
IIIa-14, IIIa-33 through IIIa-35, IlIc-9, IIIc-11, Illb-

1, IIIb-2, IIIb-7, IIIb-10 through IIIb-13, IIIb-15,
IIIb-16, and IIId-20.

-315-

The following compoiands were shown to have K±

values between 1.0 and 10.0 for Aurora-2: IIa-10, IIc-

71, IIc-75, IIc-76, IId-4, IIIa-42, IIIa-43, IIIc-10,
IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.

5 BIOLOGICAL TESTING EXAMPLE 3

CDK-2 INHIBITION ASSAY
Compoxmdis were screened In the following manner
for their ability to inhibit CDK-2 using a standard
coupled enzyme assay (Fox et al (1998) Protein Sci 7,
10 2249)'.

To an assay stock buffer solution containing
O.IM HEPES 7.5, 10 mM MgCla, . 1 mM DTT, 25 xnM NaCl, 2.5 mM
phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate
kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and

15 100 pM peptide (MAHHHRSPRKRAKKK, American Peptide,

Simnyvale, CA) was added a DMSO solution of a compound of
the present invention to a final concentration of 30 piM.
The resulting mixture was incubated at 30 ®C for 10 min.

The reaction was initiated by the addition of

20 10 VLh of CDK«2/Cyclin A stock solution to give a final
concentration of 25 nM in the assay. The rates of
reaction were obtained by monitoring absorbance at 340 nm
over a 5 -minute read time at 30 using a BioRad
Ultramark plate reader (Hercules, CA) . The Ki values were

25 determined from the rate data as a f miction of inhibitor
concentration.

The following compounds were shown to have Ki
values less than 1 |JM for C3DK-2: IIa-14, IIa-36, IIc-15,
Ilc-i25, Ilc-27, IIc-32, IIc-53, and IIIc-4.

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The following compounds- were shown to have Ki
values between 1-0 and 20.0 jlM for CDK-2: IIa-38, IIa-40,
*IIa-44, IIa-52, and IIa-54.

5 BIOLOGICAL TESTING EXAMPLE 4

ERK INHIBITION ASSAY
Compounds were assayed for the inhibition of
ERK2 by a spectrophotometric coupled- enzyme assay (Pox et
al (1998) Protein Sci 7, 2249) . In this assay, a fixed
10 concentration of activated ERK2 (10 nM) was incubated

with various concentrations of the compound in DMSO (2.5
%) for 10 min. at 30°C in 0.1 M HEPES buffer, pH 7.5,
• containing 10 mM MgCl2/ 2.5 mM phosphoenolpyruvate , 2 00
NADH, 150 ug/mL pyruvate kinase, 50 ug/mL lactate
15 dehydrogenase, and 200 erktide peptide. The reaction
was initiated by the addition of 65 pM ATP. The rate of
decrease of absorbance at 340 nM was monitored. The IC50
was evaluated from the rate data as a function, of
inhibitor concentration.
20 The following compounds were shown to have Ki

values less than 1 flM for ERK-2: IIc-15, IIC-27/ IIc-32,
IIc-53» and IIIc-4.

The following compounds were shown to have Ki
values between 1.0 and 20.0 pM for ERK-2: IIc-18, IIc-25,
25 and IIa-36.

BIOLOGICAL TESTING EXAMPLE 5
AKT INHIBITION ASSAY
Compounds were screened for their ability to
30 inhibit AKT using a standard coupled enzyme assay (Fox et
al.. Protein Sci., (1998) 7, 2249) . Assays were carried
out in a mixture of 100 mM HEPES 7.5, 10 mM MgCl2, 25 mM

-317-

NaCl / 1 mM DTT and 1.5% DMSO, Final substrate
concentrations in the assay were ^ 170 iiM ATP (Sigma
Chemicals) and 200 vM peptide (RPRAATF, American Peptide,
Sunnyvale, CA) . Assays were carried out at 30 "C and 45
5 nM AKT . Final concentrations of the components of the
coupled enzyme system were 2.5 mM phosphoenolpyruvate ,
300 NADH, 30 pg/ML pyruvate kinase and lO jig/ml
lactate dehydrogenase.

An assay stock buffer solution was prepared

10 containing all of the reagents listed above, with the

exception of AKT, DTT, and the test compound of interest.
56 ]il of the stock solution was placed in a 384 well
• plate followed by addition of 1 ul of 2 mM DMSO stock
containing the test compound (final compound

15 concentration 30 pM) . The plate was preincubated for
about 10 minutes at 30 *C. and the reaction initiated by
addition of 10 lal of enzyme (final concentration 45 nM)
and 1 mM DTT. Rates of reaction were obtained using a
BioRad Ultramark plate reader (Hercules, CA) over a 5

20 minute read time- at 30 'C, Conpouhds showing greater than
50% inhibition versus standard wells containing the assay
- mixture and DMSO without test compound were titrated to
determine IC50 values.

The following compounds were shown to have Ki

25 values between 1.0 and 20.0 pM f or AKT-3: ilc-18, . IIc-22,
IIc-25, IIC-27, IIc-31, IIC-32, IIc-37, IIC-39, IIC-42,
and Ilc-53.

BIOLOGICAIi TESTING EXAMPLE 6
30 SRC INHIBITION ASSAY

The compounds were evaluated as inhibitors of
human Src kinase using either a radioactivity-based assay
or spectrophotometric assay.

-318-

Src Inhibition Assay A; Radioactivity-base d Assay
The compotinds were assayed as inhibitors of
full length recombinant human Src kinase (from Upstate
Biotechnology, cat. no. 14-117) expressed and purified
5 from baculo- viral cells. Src kinase activity- was

monitored by following the incorporation of ^^P from ATP
into the tyrosine of a random poly Glu-Tyr polymer
substrate of composition, Glu:Tyr = 4:1 (Sigma, cat. no.
P-0275) . The following were the final concentrations of

10 the assay components: 0 . 05 M HEPES, pH 7.6, 10. mM MgCla, 2
O mM DTT, 0.25 mg/ml BSA, 10 yM ATP (1-2 liCi ^^P-ATP per

reaction), 5 mg/ml poly Glu-Tyr, and 1-2 units of
recombinant human Src kinase. In a typical assay, all
the reaction components with the exception of ATP were

15 pre-mixed and aliquoted into assay plate wells.

Inhibitors dissolved in DMSO were added to th^ wells to
give a final DMSO concentration of 2.5%. The assay plate
was incubated at 30 °C for 10 min before initiating the
reaction with ^^P-ATP. After 20 min of reaction, the

20 reactions were quenched with 150 ij1 of 10%

trichloroacetic acid (TCA) containing 20 mM Na3P04. The
O quenched samples were then transferred to a 96 -well

filter plate (Whatman, UNI-Filter GF/F Glass Fiber
Filter, cat no. 7700-3310) installed on a filter plate

25 vacuum manifold. Filter plates were washed four times

with 10% TCA containiiig 20 mM Na3P04 and then 4 times with
methanol. 200vil of scintillation fluid was then added to
each well. The plates were sealed and the amoxant of
radioactivity associated with the filters was quantified

30 on a TopCount scintillation counter. The radioactivity
incorporated was plotted as a function of the inhibitor
concentration. The data was fitted to a competitive
inhibition kinetics model to get the Ki for the compound.

-319-

Src Inhibition Assay B; Spectrophotometric Assay
The ADP produced f rom ATP by the hximan
recombinant Src kinase -catalyzed phosphorylation of poly
Glu-Tyr substrate was quanitified using a coupled enzyme
assay (Fox et al (1998) Protein Sci 1 , 2249) . In this
assay one molecule of NADH is oxidised, to NAD for every
molecule of ADP produced in the kinase reaction* The
disappearance of NADH can be conveniently followed at 340
nrai.

The following were the final concentrations of
the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgC12,
2 mM DTT, 0.25 mg/ml , poly Glu-Tyr, and 25 nM of
■ recombinant human Src kinase • Final concentrations of the
components of the coupled enzyme system were 2.5 mM
phosphoenolpyruvate, 200 yM NADH, 30 yg/ml pyruvate
kinase amd 10 iig/ml lactate dehydrogenase.

In a typical assay, all the reaction components
with the exception of ATP were pre-mixed and aliquoted
into assay plate wells. Inhibitors dissolved in DMSO
were added to the wells to give a final DMSO concentration
of 2.5%. The assay plate was incubated at 30 for 10 m±n
before initiating the reaction with 100 pM ATP. The
absorbance change at 340 nm with time, the rate of the
reaction, was monitored on a molecular devices plate
reader. The data of rate as a function of the inhibitor
concentration was fitted to corapettive inhibition
kinetics model to get the Ki for the compoimd.

The following compounds were shown to have a Ki
value of <100nM on SRC: IIa-8, IIa-21, IIa-23, IIa-24,
IIa-27, IIa-28, IIa-30 through lla-33, IIb-1, IIb-4, lib-
5, IIC-3, IIC-8, IIC-10, IIC-13, IIC-15, IIC-18, Ii;c-19,
IIc-21 through IIc-24, Ilc-31 through IIc-35, IIc-37

-320-

through lIc-3&, IIc-41 through IIc-44, IIc-51, IId-1,
IId-2, IIIa-1, lIIa-6 through HIa-8, IIIa-26 through
II±a-30, and IIIc-1 through IIIc-5.

The following compounds were shown to have a Ki
5 value of between lOOnM and IjiM for SRC: IIa-1; IIa-2,
IIa-7, IIa-9,. IIa-12, Ila-14, IIsL-22, IIa-25, IIa-26,
IIa-29, IIa-34 through IIa-42, IIa-46, IIa-47, IIa-49
through IIa-52, IIa-56, IIa-57, IIa-59, IIa-61, IIa-62,
IIa-66, IIa-67, IIa-69, IIa-72, IIa-73, IIa-75, IIb-6,

10 IIb-8, IIc-4 through IIc-7, IIc-9, Ilc-11, IIc-i2, lie-
14., ilc-16, IIc-17, IIc-20, IIc-25 through IIc-30, lie-
36, Ilc-40/ IIc-46 through IIc-50, IIc-52 through IIc-61,
IIc-63 through IIc-65, IIc-67, IIc-69, IId-3, IIIa-2
through Ilia -5, IIIa-11, IIIa-14 through IIIa-18, IIIa-22

15 through Ilia- 24, IIIa-31, IIIa-33, IIIa-35, IIIa-38
through IIIa-43, and IIIa-47.

The following compounds were shown to have a Ki
value of between ipM and 6\XM for SRC: IIa-13/ IIa-20^
IIa-44, IIa-45, Ilar48, IIa-54, IIa-55, IIa-63, IIa-65,

20 IIa-68, IIa-70, IIa-71, IIa-74, IIa-77, IIa-78, IIa-81,
IIb-3, IIb-9> IIc-1/ IIc-2, IIc-66, IIc-68, IIIa-13,
O llla-2l/ IIIa-25, IIIa-34, lIIa-36, IIIa-37, and IIIa^44.

While we have presented ^ number of embodiments
of this invention, it is apparent that our basic

25 construction can be altered to provide other embodiments
which utilize the compounds and methods of this
invention • Therefore, it will be appreciated that the
scope of this invention is to be diafined by the appended
claims rather than by the specific embodiments which have

30 been represented by way of example.

-321-

We claim;

1. A compoiind of formula IIc:

lie

or a phannaceutically acceptable derivative or prodrug

thereof , wherein ;

and are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring, having 0-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein any
substi tut able carbon on said fused ring formed by R""
and R^ is substituted by oxo, T-R^, or L-Z-R^, and any
substitutable nitrogen on said ring formed by R"" and R^
is substituted by R^;
is T- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein Ring D is
substituted at any sxabstitutable ring carbon by oxo,
T-R^, or V-Z-R^, and at any substitutable ring nitrogen
by -R*;

-322-

T is a valence bond or a Cx-4 alkylidene chain;
Z is a Ci-4 alkylidene chain;

L is -O.-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R^)-,
-N(R^)-, -CO-, -CO2-, -N(R^)CO-, -N{R^)C(0)0-,
-N(R^)CON(R^)-, -N(R^) S02N(R«)-, -N (R^) N (R^) - ,
-C(0)N(R^)- , -OC(0)N(R^) -, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R^)2S02-, -C(R^)2S02N{R^) -, -C (R^) 2N (R^) - ,
•-C(R^) 2N(R^)C(0)-, -C(R^)2N(R^)C(0) Q-, -C (R^) =NN (R^) - ,
-C(R*)=N-0-, -C(R^)2N(R^)N(R^)-, -C (R^) 2N (R^) SO2N (R^) - , or
-C (R*) 2N (R^) CON (R^) - ;

R^ and R^' are independently selected from -R, -T-W-R^, or
R^ and R^' are taken together with their intervening
atoms to form a fused, 5-8 membered, \insaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable carbon on said fused ring formed by R^
and R^' is substituted by halo, 0x0, -CN, -NO2, -R''/ or
-V-R^, and any substitutable nitrogen on said ring
formed by R^ and R^' is substituted by R*;

R^ is selected f?:om -R, -halo, -OR, -C(=0)R, -CO2R,
-COCOR, -COCH2COR, -NO2, -CN, -S(0)R, -S(0)2R/ -SR,
-N(R*)2, -CON(r')2, -S02N(R'')2, -0C(=0)R, -N(R'')C0R,
-NCR') C02(Ca.6 aliphatic) , -N{R*)N(R*)2, -C=NN(R*)2,
-C=N-OR, -N(R')C0N{R'')2, -N(R')S02N(R'')2, -N(R*)S02R, or
-0C(=0)N(R')2;

each R is independently selected from hydrogen or an
optionally substituted group selected from Ci_6
aliphatic, Ce-io aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R"* is independently selected from -R'', -COR'',

-CO2 (optionally substituted Ci-g aliphatic) , -C0N (r'')2,
or -SO2R';

-323-

each ±s independently selected from -R, halo, -OR,

-C(=0)R, -CO2R, -COCOR, -NO2, -CN, -S(0)R, -SO2R, -SR,
-N(R*)2, -CON(R^)2, -S02N(R^)2, -OC{=0)R, -N(R^)COR,
-N(R^) C02 { optionally siibstituted Ci-s aliphatic) ,
-N(R*)N(R'*)2, -C=NN(R^)2, -C=N-OR, -N (R'*) CON (R'') 2,
-N(R^)S02N{R*)2, -N(R^)S02R, or ^OC (=0) N (R*) 2 ;

V is -0-, -S-, -SO-, -SO2-, -N(R^)S02-, -S02N(R^)-,
-N(R*)-, -CO-, -CO2-, -N(R^)CO-, -N(R^)C(0)0-,
-N(R«)CON(R«)-, -N(R^)S02N(R^) -, -N (R*') N (R^) - ,
-C(0)N(R^)-, -OC(0)N(R*)-, -C(R^)20-, -C(R^)2S-,
-C(R^)2SO-, -C(R^)2S02-, -C{R«)2S02N(R^)-, -C (R^) 2N (R^) - ,
-C(R«) 2N(R*)C(0)-, -C(R«)2N(R«)C(0)0-, -C (R^) =NN (R^) - ,
-C(R*)=N-0-, -C(R*)2N(R^)N(R^)-, -C (R^) 2N (R*) SO2N (R^) - , or
-C(R®)2N(R^)CON(R®)-; i

W is -C(R^)20-, -C(R*)2S-, -C(R^)2SO-, -C(R*)2S02-,
-C(R«)2S02N(R*) -, -C(R^)2N(R^)-, -CO-, -CO2- ,
-C (R^) OC (O) - , -C(R^)OC(0)N(R^)^, -C (R*) 2N (R^) CO- ,
-C(R^)2N{R*)C(0)0-, -C(R*)=NN(R®) -, -C(R*)=N-0-i
-C(R*)2N(R*)N(R^)-, -C(R^)2N(R*)S02N{R«)-,
-C(R*)2N(R*)CON(R*)-, or -CON(R^)-;

each R* is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R®
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and

each r' is independently selected from hydrogen or an
optionally substituted C1.6 aliphatic group, or two R''
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.

-324-

2. The compoiHid according to claim 1, wherein said
compound has one or more features selected from the group
consisting of :

(a) R"" and are taken together with their

intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein any substitutable
carbon on said fused ring formed by R"" and R^ is
substituted by oxo, T-R^ or L-Z-R^, and any
substitutable nitrogen on said ring formed by R"^
and R^ is substituted by R^;

(b) R^ is T- (Ring D) , wherein T is. a valence bond or
a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(d) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
substituted benzo ring; and

(e) R^ is selected from -R, -halo, -OR, or -N(R*)2.

3. The compound according to claim 2, wherein:
(a) R'*' and R^ are taken together with their

intervening atoms to form a fused. Unsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein any substitutable
carbon on said fused ring formed by R^" and R^ is
substituted by oxo, T-R^, or L-Z-R^ and any
substitutable nitrogen on said ring formed by R"^
and R^ is substituted by R^;

-325-

is T- (Ring D) , wherein T is a valence bond or
a methylene unit;

Ring D is a 5-7 meinbered monocyclic ring pr an
8-10 merabered bicyclic ring selected from an
aryl or heteroaryl ring;

r2 is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
substituted benzo ring; and

R^ is selected from -R, -halo, -OR, or -N(R^)2-

4. The compound according to claim 2, wherein said
compound has one or more features selected from the group
consisting of:

(a) R* and R^ are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piper idino, or imidazo ring;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-e aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(d) R^ is selected from -R, -halo, -OR, or -N(R^)2#
wherein R is selected from hydrogen, Ci-6
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R*)- .

(b)
(c)

(d)

(e)

5. The compound according to claim 4, wherein:

-326-

(a) R"" and are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(d) R^ is selected from -R, -halo, -OR, or -N(R*)2/
wherein R is selected from hydrogen, Ci-e
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -O- , -S-,
or -N(R^)

6, The compound according to claim 4, wherein said
compound has one or more features selected from the group
consisting of:

(a) R"" and R^ are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;

(b) R^ is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

(c) R^ is hydrogen or C1-4 aliphatic and R^' is
hydrogen;

(d) R^ is selected from -R, -OR, or -N(R*)2, wherein
R is selected* from hydrogen, Ci-e aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is stabstituted by up to three
siabstituents selected from -halo, -CN, -NO2,

-327-

-N(R^)2/ optionally siibstituted Ci-e aliphatic
group, -OR, -C{0)R, -CO2R, -CONH(R*), -N(R^)COR,
-N(R^)C02R, -S02N(R*)2r -N(R*)S02R,
-N{R^)C0CH2N(R^>2, -U{R^)C0CH2CH2N(R*)2/ or
-N(R^)C0CH2CH2CH2N(R'')2/ wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
meinbered heteroai^l ring, or a 5-6 membered
heterocyclic ring.

7. The compound according to claim 6, wherein:

(a) R"" and are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;

(b) R^ is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring ;

(c) R^ is hydrogen or C1-4 aliphatic and R^' is
hydrogen;

(d) R^ is selected from --R, -OR, or -N(R^)2/ wherein
R is selected from hydrogen, Ci-e aliphatic, 5-6
membered heterocyclyl , phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

(e) Ring D is substituted by up to three
substituents selected from -halo, -CN, -NO2/
-N(R*)2/ optionally substituted Ci-e aliphatic
group, -OR, -C(0)R, -CO2R, -CONH(R^), -N(R^)COR,
-N(R*)C02R, -S02N(R^)2, -N{R^)S02R,
-N(R^)COCH2N(R*)2, -N(R^)C0CH2CH2N{R*)2, or
-N(R^)C0CH2CH2CH2N(R*)2, wherein R is selected
from hydrogen, Ci-e aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

-328-

8. The compound according to claim 1, wherein and
are taken together with their intervening atoms to form
a fused benzo ring, wherein any subs ti tut able carbon on
said fused ring, formed by R"" and R^ is substituted by T-
R^, or li-Z-R^-

The compound according to claim 8, wherein:
R^ is T~ (Ring D) , wherein T is a valence bond or
a methylene unit;

Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;
r2 is -R or -T-W-R^ and R^' is hydrogen; or R^ and
r"* are taken together to form an optionally
substituted benzo riiig; and

R^ is selected from -R, -halo, -OR, . or -N{R*)2-

10. The compound according to claim 9, wherein:

(a) R^ is T- (Ring p) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(b) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and

(c) R^ is selected from -R, -halo, -OR, or -N(R*)2/
wherein R is selected from hydrogen, Ci-e
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N{R^)-.

9.
(a)

(b)

(c)

(d)

11. The compound according to claim 10, wherein:

-329-

(a) is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

(b) is hydrogen or C1-4 aliphatic and R^' is
hydrogen;

(c> R^ is selected from -R, -OR, or -N(R^)2r wherein
R is selected from hydrogen, Ci-s aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH-; and

{d> Ring D is snbstituted by up to three

siabstituents selected from -halo, -C3Sr, -NO2,
-N(R^)2/ optionally substituted Ci.e aliphatic
group, -OR, -C(0)R, -CO2R, -CONH(R^), -N(R^)COR,
-N(R^)C02R, -S02N(R^)2. -N(R^)S02R,
-N(R^)C0CH2N(R-)2. -N(R^)COCH2CH2N(R^)2, or
-N(R^)COCH2CH2CH2N{R*)2/ wherein R is selected
from hydrogen, Ci-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring-

12. The compoxind according to claim 1, wherein R^
and R^ are taken together with their intervening atoms to
form a fused, unsaturated or partially unsaturated, 5-7
membered ring having 0-3 ring heteroatoms selected from
oxygen, sulfur, or nitrogen, wherein any substitutable
carbon on said fused ring formed by R'' and R^ is
substituted by 0x0, T-R^, or L-Z-R^ and any substitutable
nitrogen on said ring formed by R^ and R^ is substituted
by R^; provided that said fused ring formed by R^" and R^
is other than benzo.

13. The compound according to claim 12, wherein:

-330"

(a) R"* and are taken together with their
intervening atoms to form a fused, rmsaturated
or partially lansaturated, 5-6 membered ring
having 1-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, or a partially unsaturated
6 -membered carbocyclo ring, wherein any
substitutable carbon on said fused ring formed
by R^ and R^ is substituted by oxo, T-R^, or L-Z-
R^, and any substitutable nitrogen on said ring
formed by R*' and R^ is siibstituted by R*;

(b) R^ is T- (Ring D) , wherein T is a valence bond or
a methylene \init, and Ring D is a 5-7 membered
monocyclic or an 8-10 membered bicyclic aryl or
heteroaryl ring;

(c) R^ is -R or -T-W-R^ and R^' is hydrogen; or R^ and
R^' are taken together to form an optionally
substituted benzo ring; and

(d) . R^ is selected from -R, -halo, -OR, or -N(R^)2.

14. The compound according to claim 13, wherein:

(a) R^ and R^ are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring, wherein any
substitutable carbon on said fused ring formed
by R* and R^ is substituted by oxo, T-R^, or L-Z-
R^, and any substitutable nitrogen on said ring
foinned by R"" and R^ is substituted by R^;

(b) R^ is T- (Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) R^ is -R and R^' is hydrogen, wherein R is
selected from hydrogen, Ci-s aliphatic, phenyl, a

5-6 membered heteroaryl ring , or a 5-6 meitibered
heterocyclic ring; and
(d) is selected from -R, -halo, -OR, or -N(R*)2/
wherein R is selected from hydrogen, Ci-e
aliphatic, or 5-6 membered heterocyclyl , phenyl,
or 5-6 membered heteroaryl, and L is -0-, -S-,
or -N(R*)-.

15. The compound according to claim 14, wherein:

(a) R"" and R^ are taken together to form a pyrido,
piperidino, or cyclohexo ring, wherein any
siibstitutable carbon on said fused ring formed
by R"" and R^ is substituted by oxo, T-R^, or L-Z-
R^, and any substitutable nitrogen on said ring
formed by R"" and R^ is' substituted by R^;

(b) R^ is T-Ring wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

(c) R^ is hydrogen or C1-4 aliphatic and R^' is
hydrogen;

(d) R^ is selected from -R, -OR, or -N(R^)2/ wherein
R is selected from hydrogen, Ci-e aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is -0-, -S-, or -NH- ; and

(e) Ring D is substituted by up to three
siabstituents selected from -halo, -CN, -NO2,
-N(R^)2, optionally substituted Ci-g aliphatic
group, -OR, -C(0)R, -CO2R, -CONH(R^), -N(R^)COR,
-N(R*)C02R, -S02N(R^)2/ -N(R^)S02R,
-N(R^)COCH2N(R*)2, -N(R^)C0CH2CH2N(R^)2, or
-N(R^)COCH2CH2CH2N{R*)2/ wherein R is selected
from hydrogen, Ci-6 aliphatic, phenyl, a 5-6

-332-

membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

±6. A compound selected from the grotip consisting

of:

{2- [ (2-Hydroxyethyl)phenylamino] -quina2olin-4-yl} - (5-

me thyl - 2H-pyrazol - 3 -yl ) - amine ;

[2- (Methylphenylamino) -quinazolin-4-yl] - (5-methyl-2H-

pyrazol - 3 -yl ) - amine ;

(5-methyl-2H-pyrazol-3-yl) -{2-r [N-methyl-N- (pyridin-3-

ylmethyl) amino] -quinazolin-4-yl} -amine ;

(5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino-quinazolin-4-
yl ) -amine ;

(2-Benzylaraino-quinazolin-4-yl) - (5-methyl-2H-pyrazol-3-
y 1 ) - amine ;

(2-Cyclohexylamino-quinazolin-4-yl) - (5 -methyl -2H-*

pyrazol - 3 -yl ) -amine ;

[2- {2,3-Dihydrobenzo[l,4]dioxin-6-ylamino) -quinazolin-

4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine;

(2-Cyclohexylmethylamino-quinazolin-4-yl) - (5 -methyl- 2H

pyrazol-3-yl) -amine;
[2- (lH-Indazol-6-ylamino) -quinazolin-4-yl] - (5-methyl-

2H-pyrazol - 3 -yl ) - amine ;

(5-Methyl-2JJ-pyrazol-3-yl) - [2- (pyridin-3-

ylmethylamino) -quinazolin-4-yl] -amine;

[2- (3-Chlorophenylamino) -quinazolin-4-yl] - (5-methyl-2H

pyrazol-3-yl) -amine;
[2- (4-Chlorophenyl amino) -quinazolin-4-yl] - (5-methyl-2H

pyrazol-3-yl) -amine;

[2- {4-Fluorobenzylamino) -quinazolin-4-yl] - (5-methyl-2H

pyrazol-3-yl) -amine;

-333-

{2- [2- (2-Hydroxyethyl)phenylamino] -quinazolin-4-yl} - (5-
methyl -2H-pyrazol- 3 -yl) -amine ;

[2- (4-Cyanomethylphenylamino) -quinazolin-4-yl] - (5-
methyl-2H-pyrazol-3-yl) -amine;

[2- (3-Hydroxymethylphenylamino) -quina2olin-4-yl] - (5-
methyl - 2H-pyrazol - 3 -yl ) -amine ;

[2- (3-Hydroxyphenylamino) -quinazolin-4-yl] - (5-methyl-
2H-pyrazol - 3 -yl ) - amine ;

( 5 - Cyclop ropyl - 2H-pyrazol - 3 -yl ) - (2 -phenylamino-
quinazolin-4-yl) -amine;
(5-Cyclopropyl-2i^-py2^azol-3-yl) - [2- (3-
methylphenyl amino) -quinazolin-4-yl] -amine;

(5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (6-methoxypyridin-3-
ylamino) -quinazolin-4-yl] -amine;

(5-Cyclopropyl-2if-pyrazol-3-yl) - [2- (indan-5-ylamino) -
quinazolin-4-yl] -amine;

(5-Cyclopropyl-2H-pyrazol-3-yl) - [2- {lH-indol-6-
ylamino) -quinazolin-4-yl] -amine;

[2- (4-Acetamido-3^methLylphenylamino) -quinazolin-4-yl] -
( 5 - cyclopropyl - 2H-pyrazol - 3 -yl ) - amine ;

[2- (4-Chloro-3-methylphenylamino) -quinazolin-4-yl] - (5-
cyclopropyl - 2H-pyrazol -3 -yl ) -amine ;

(5 -Cyclopropyl -2H-pyrazol- 3 -yl) - [2 - (4-
ethylphenylamino) -quina2olin-4-yl] -amine;

( 5 - Cyclopropyl - 2H-pyrazol - 3 -yl ) - [2 - { 4 -
propylphenylamino) -cpiinazolin-4-yl] -amine;

( 5 -Cyclop ropyl -2H-pyrazol- 3 -yl) - {2-[4-{2-
hydroxyettiyl ) phenylamino] -quinazolin-4 -yl } -amine ;

(5-Cyclopropyl-2H-pyrazol-3-yl) - (2-phenetylamino-
quina2olin-4-yl) -amine;

[2- (2-Cyclohexylethylamino) -quinazolin-4 -yl] - (5-
cyclopropyl - 2iI-pyrazol - 3 -yl ) -amine ;

-334-

[2- (4-Carboxymethoxyphenylamino) -quinazolin--4-yl] -
cyclopropyl - 2H-pyrazol - 3 -yl ) - amine ;

[2- (4-Cyanomethylphenylaraino) -quinazolin-4-yl] - (5-
cyclopropyl - 2H-pyrazol -3 -yl ) -amine ;

[2- (Benzotliiazol-6-ylamino) -quinazolin-4-yl] - (5-
cycl opropyl - 2H-pyrazol - 3 -yl ) - amine ;

(5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3,4-
dimethylphenylamino) -quinazolin''4~yl] -amine;

(5 -Cyclopropyl -2H-pyrazol- 3 -yl) - [2- (2-
phenoxye thy 1 amino) -quinazolin-4-yl] -amine;

(5 -Cyclopropyl -2H-pyrazol -3 -yl) - [2- ( ttiiophen-2-
methylamino) -quinazolin-4-yl] -amine;

[2- (4-Carboxymethylp3ienylamino) -quinazolin-4-yl] - (
cyclopropyl - 2H-pyrazol - 3 -yl) - amine ;

(5 -Cyclopropyl -2H-pyrazol- 3 -yl) - [2- (lH-indazol-5-
ylamino) •^quinazolin-4-yl] -amine;

( 5 -Cyclopropyl -2H-pyrazol -3 -yl) - [2- (pyridin-3-
ylmethylamino) -quinazolin-4-yl] -amine;

(5 -Cyclopropyl -2H-pyrazol- 3 -yl) - [2- (3-
methoxycarbonylphenylamino) -quinazolin-4-yl] -amine;

[2- (3-Carboxyphenylamino) -quinazolin-4-yl] - (5-
cyclopropyl - 2H-pyrazol - 3 -yl ) - amine ;

{5 -Cyclopropyl -2H-pyrazol- 3 -yl) - [2- (3-
ethylphenylamino) -quinazolin-4-yl] -amine;

( 5 -Cyclopropyl - 2H-pyrazol- 3 -yl) - [2- (2,3-
dimethylphenylamin6) -quinazolin-4-yl] -amine;

(5 -Cyclopropyl -2H-pyrazol- 3 -yl) - [2- (3,4 -
dime thoxyphenyl amino) -quinazolin-4-yl] -amine;

{5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3-
methoxyphenylamino) -quinazolin-4-yl] -amine ;

(5-Methyl"2H-pyrazol-3-yl) - ( 2 -phenyl amino - 5, 6, 7, 8-
tetrahydroquinazolinin-4-yl) -amine;

-335-

[2- (Biphenyl-3-ylamino) -quinazolin-4-yl] - (5-
cyclopropyl-2H-pyra2ol-3-yl) - amine ;

(5-Cyclop3ropyl-2H-pyrazol-3-yl) - [2- (3-plienylprop-l-
ylamino) -quinazolin-4-yl] -amine;

[2- (4-acetamido-3-methylphenylamino) -quinazolin-4-yl] -
( 5 -methyl - 2H-pyrazol - 3 -yl ) - amine ;

(5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (indan-2-ylamino) -
quinazolin-4-yl] -amine;

[2- (3-Methylptienylamino) -quinazolin-4-yl] - (5-methyl-2H

pyrazol - 3 -yl ) - amine ;

[2- {2-Chloro-5-methylphenylamino) -quinazolin-4-yl] - (5-

methyl -2H-pyrazol -3 -yl) -amine;

(5-Cyclopropyl-2H-pyrazol-3-yl) -{2- [4- (morpholin-1-
yl) phenylaraino] -quinazolin-4 -yl } -amine ;

[2- (Benzothiazol-6-ylamino) -quinazolin-4 -yl] - (5-methyl
2H-pyrazol - 3 - yl ) - amine ;

[2- (3,4-Dimethylphenylamino) -quinazolin-4-yl] - (5-
methyl - 2H-pyrazol - 3 -y 1 ) - amine ;

[2- (3-Ethylphenylamino) -quinazolin-4-yl] - ( 5 -methyl - 2H-
pyrazol-3-yl) -amine;

[2- (3-Methoxyphenylamino) -quinazolin-4 -yl] - (5-methyl-

2H-pyrazol-3-yl) -amine;

[2- (4-Acetamido-3-cyanophenylamino) -quinazolin-4 -yl] -
(5-methyl-2H-pyrazol-3-yl) -amine ;

[2- (2-Methoxybiphenyl-5-ylamino) -quinazolin-4-yl] - (5-
metliyl-2H-pyrazol-3-yl) -amine;

[2- (4-Acetamidophenylamino) -quinazolin-4 -yl] - (5-methyl
2H-pyrazol-3-yl) -amine;

[2- (4- tejTt-Butoxycarbonylamino-phenylamino) -quinazolin

4-yl] - (5-methyl-2Jir-pyrazol-3-yl) -amine;

[2- (4-Cyanophenylamino) -quinazolin-4-yl] - {5-methyl-2H-
pyrazol-3-yl) -amine;

(5-Methyl-2H-pyrazol-3-yl) - [2- (6-0x0-6 , 10b-dihYdro-4aH-

benzo [c] cliromen-2-ylamino) -quinazolin-4-yl] -amine;

[2- (Biphenyl-3-ylamino) -quinazolin-4-yl] - (5 -methyl -2H-

pyrazol - 3 -yl ) - amine ;

[2- (4-Methoxycarbonylmethyl-3-methylphenylamino) -

quinazolin-4-yll- (5-methyl-2H-pyrazol-3-yl) -amine;

[2- (4-Carboxymethyl-3-methylphenylamino) -quinazolin-4-
yl] - (5-met:hyl-2H-pyrazol-3~yl) -amine;

[2- (4-Aminophenylamino) -quinazolin-4-yl] - (5-methyl-2H-

pyrazol - 3 - y 1 ) - amine ;

[2- (4-Bromoplienylamino) -quinazolin-4-yll - ( 5 -methyl -2ir-

pyrazol - 3 -yl ) - amine ;

[2- (4-Isobutyrylamino-phenylamino) -quinazolin-4-yl] - (5-

methYl-2H-pyrazol-3-yl) -amine;

(5-Ethyl-2H-pyrazol-3-yl) - [2- (5-ethyl-2H-pyrazol-3-
ylamino) -quinazolin-4-yl] -amine;

(lH-Indazol-3-yl) - (2-phenylamino-quinazolin-4-yi ) -

amine ;

(lH-Indazol-3-yl) - [2- (3-trif luoromethylphenylamino) -
c[uinazolin-4-yl] -amine;

(lH-Indazol-3-yl) - [2- (4 -tr if luoromethylphenylamino) -

quinazolin-4-yl] -amine;

[2- (Adamantan- 2 -ylamino) -quinazolin-4-yl] - (IH-indazol-

3-yl) -amine;

(lH-Indazol-3-yl) - ( 2 -methyl -phenyl -amino-quinazolin-4 -
yl) -amine;

[2- ( 2 -Chi or o- phenyl) -amino-quinazolin-4 -yl] - (IH-
indazol - 3 -yl) - amine ;

(lH-Indazol-3-yl) - [2- (2 -trif luoromethylphenylamino) -

quinazolin-4-yl] -amine;

[2- (4-Cyanomethylphenylamino) -quinazolin-4-yl] - (IH-

indazol-3-yl) -amine;

[2- (4-Chlorophenylatnino) -5,6,7,8-
tetrahydroquinazolinin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -

amine;

(5-Methyl-2H-pyra2ol-3-yl) - (2-phenylamino-6 , 7 , 8 , 9-
t e t rahydro- 5H- cyclohep t apyr imidin- 4 -yl ) - amine ;

[2- (Ben2imidazol-2-ylamino) -7-benzyl-5, 6,7, 8-
tetrahydro-pyrido [3 , 4-d]pyrimidin-4-yl] - (5-methyl-2K-
pyrazol-3-yl) -amine;

( 7 -Benzyl - 2 -phenylamino- 5,6,7,8- te trahydro-pyrido [3,4-
d] pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) -amine;

[6-Benzyl-2- (4-chlorophenylamino) -5, 6 , 7 , 8- te trahydro-
pyrido [4 , 3-d] pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -
amine;

[2- (Ben2imidazol-2-ylamino) -6-benzyl-5, 6,7,8-
tetrahydro-pyrido [4, 3-d]pyrimidin-4-yl] - (5 -methyl -2H-
pyrazol - 3 - yl ) - amine ;

( 6 -Benzyl - 2 -phenylamino- 5 ,6,7,8- te trahydro-pyrido [4,3-
d]pyrimidin-4-yl) - (5-methyl-2H-pyrazol-3-yl) -amine;

(5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino-5 , 6 , 7 , 8-
tetrahydro-pyrido [3 , 4-d]pyrimidin-4-yl) -amine;

[2- (4-Cyanomethylphenylamino) -quinazolin-4-yl] - (IH-
pyrazolo [3 , 4 -b] pyridin-3-yl) -amine;

[2- (4-Cyanobenzylamino) -quina2olin-4-yl] - (IH-
pyrazolo [3 , 4 -b] pyridin-3 -yl ) -amine ;

[2- (4-Cyanomethylphenylamino) -quinazolin-4-yl] - (4-
f luoro-lH-indazol-3-yl) -amine;

[2- (4-Cyanophenylamino) -quinazolin-4-yl] - {lH-indazol-3

y 1 ) - amine ; and

[2- (4-Cyanobenzylamino) -quinazolin-4-yl] - (lH-indazol-3

yl) -amine.

-338-

17. A composition comprising a compound according
to any one of claims 1-16, and a pharmaceutically
acceptal>le carrier.

18. Th.e composition according to claim 17 , furth.er
comprising, an additional therapeutic agent.

19. A method of inhil>iting Aurora-2, GSK-3, Src,
ERK-2, or AKT activity in a biological sample comprising
the step of contacting said biological sample with a
compoimd according to any one of claims 1-16.

20. A method of inhibiting Aurora-2 activity in a
patient comprising the step of administering to said
patient a composition according to claim 17.

21. A method of inhibiting Aurora-2 activity in a
patient comprising the step of administering to said
patient a composition according to claim 18.

22. A method of treating an Aurora- 2 -mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amoiint of a composition according to claim 17.

23 . The method according to claim 22 , wherein said
disease is selected from colon, breast, stomach, or
ovarian cancer.

24. The method according to claim 23, wherein said
method further comprises administering an additional
therapeutic agent.

-33&-

25. The method according to claim 24, wherein said
additional therapeutic agent is a chemotherapeutic agent.

26. A method of inhibiting GSK-3 activity in a
patient comprising the step of administering to said
patient a composition according to claim 17.

27. A method of inhibiting GSK-3 activity in a
patient comprising the step of administering to said
patient a composition according to claim 18.

*

28 . A method of method of treating a GSK-3 -mediated
disease, which method comprises administering to a
patient in need of such a treatment a therapeutically
effective amoimt of a composition according to claim 18.

29. The method according to claim 28, wherein said
GSK-3 -mediated disease is selected from diabetes,
Alzheimer's disease, Huntington's Disease, Parkinson's
Disease, AIDS-associated dementia, amyotrophic lateral
sclerosis (AML) , multiple sclerosis (MS) , schizophrenia,
cardiomycete hypertrophy, reperf usion/ischemia, or
baldness .

30- The method according to claim 29, wherein said
G&K- 3 -mediated disease is diabetes.

31. A method of enhancing glycogen synthesis or
lowering blood levels of glucose in a patient in need
thereof, which method comprises administering to said
patient a therapeutically effective amount of a
composition according to claim 17.

-340-

32. A method of inhibiting the production of
hyperphosphorylated Tau protein in a patient, which
method comprises administering to a patient in need
thereof a therapeutically effective amount of a
composition according to claim 17 .

33. A method of inhibiting the phosphorylation of
p-catenin, which method comprises administering to a
patient in need thereof a therapeutically effective
amount of a composition according to claim 17.

34. A method of inhibiting Src activity in a
patient comprising, the step of administering to said
patient a composition according to claim 17.

35. A method of treating a Src -mediated disease,
which method comprises administering to a patient in need
of such a treatment a therapeutically effective amount of
a composition according to claim 17.

36. A method of inhibiting ERK-2 activity in a
patient comprising, the step of administering to said
patient a composition according to claim 17.

37. A method of treating an ERK-2 -mediated disease,
which method comprises administering to a patient in need
of such a treatment a therapeutically effective amount of
a composition according to claim 17.

38. A method of inhibiting AKT activity in a
patient comprising the step of administering to said
patient a composition according to claim 17.

-341-

39. A method of treating an AKT-mediated disease,
which method cotiqprises administering to a patient in need
of such a treatment a therapeutically effective amount of
a composition according to claim 17.

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization
International Bureau

(43) International Publication Date
27 June 2002 (27.06.2002)

PCT

(10) International Publication Number

wo 02/050065 A3

(51) International Patent Classification^: C07D 403/12,
A61K 31/517, 31/519, C07D 401/14, 405/14, 403/14.
417/14, 409/14, 471/04, A61P 35/00

(21) International Application Number: PCT/USO 1/49 140

(22) International Filing Date:

19 December 2001 (19.12.2001)

English
English

(25) Filing Language:

(26) Publication Language:

(30) Priority Data:

60/257,887 21 December 2000 (21.12.2000) US

60/286,949 27 April 2001 (27.04.2001) US

(71) Applicant (for all designated States except US): VERTEX
PHARMACEUTICALS INCORPORATED [USAJS];
Patent Department, 130 Waverly Street, Cambridge, MA
02139-4242 (US).

(72) Inventors; and

(75) Inventors/Applicants (for US only): BEBBINGTON»
David [GB/GB]; 6 Linden Close, Newbury, Bericshire
R6141QA (GB). CHARRIER, Jean-Damien [FR/GB];
Vertex Phannaceuticals Inc., Cottage Wing, Station Road,
Southam, Bishops Itchington, Oxfonishire CV47 2QB
(GB). DAVIES, Robert [GB/US]; 65 Orient Avenue,
Arlington, MA 02474 (US). EVERITT, Simon [GB/GB];
10 Bell Close, Beaconsfield, Buckinghamshire HP9 lAT
(GB). KAY, David [GB/GB}; 4 Church Path, Purton,
Wiltshire SN5 9DR (GB). KNEGTEL, Ronald [DK/GB];

92 Andersey Way, Abingdon, Wiltshire OX 14 5NW (GB).
PATEL, Sanjay [GB/GB]; 2 Allder Close, Abingdon,
Wiltshire OX 14 1 YG (GB).

(74) Agents: SILVERMAN, Ian et al.; Vertex Phannaceuti-
cals Inc., 130 Waveriy Street. Cambridge, MA 02139^242
(US).

(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM. DZ, EC, EE, ES, H, GB, GD, GE, GH,
GM, HR, HU, ID, IL, IN, IS. JP, KE. KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV. MA, MD, MG, MK, MN. MW,
MX, MZ, NO, NZ, PH, PL, PT, RO. RU, SD. SE, SG, SI,
SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU,
ZA, ZW.

(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW).
Eurasian patent (AM, AZ, BY. KG, KZ, MD, RU, TJ, TM),
EiMDpean patent (AT, BE, CH. CY, DE, DK, ES, FT, FR,
GB, GR. IE. IT, LU, MC, NL, PT, SE, TR), OAPI patent
(BF, BJ, CF, CG. a, CM. GA. ON, GQ. GW, ML, MR,
NE, SN, TD, TG).

Published:

— with international search report

(88) Date of publication of the international search report:

24 October 2002

For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begins
ning of each regular issue of the PCT Gazette.

(54) Title: PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS

IT)

O

(lie)

(57) Abstract: This invention describes novel pyrazole compound of formula (He): wherein R*
is T~Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8- 10 membered bicyclic ring
selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R» and R^ are taken together with their
intervening atoms to fom a fused, unsaturated or partially unsaturated, 5-7 membered ring having
0-3 heteroatoms; and R^ and R^' are as described in the specification. The compounds are useful
as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases
such as cancer, diabetes and Alzheimer's disease.

BEST AVAIIuABL£ COPY

INTERNATIONAL SEARCH REPORT

Intei^Bpnal Applleallea No

PCT7US 01/49140

\prr'^tmfof^"""^K31/S17 A61K31/519 C07D401/14 C07D405/14
C07D403/14 C070417/14 C07D409/14 C07D471/04 A61P35/00

Acieordlng totiileinalional Patent Clamairailinn (IPC) Of to boUi walkioalclasslflealkw

a HEUSS SEARCHED

Minimum documentatton searched (dassiTical'on system fo*w»ed by elassilicalion aymb^

IPC 7 C07D A61K A61P

Documertalion searched other than minimum documentation to the extent that such documante are ineludsd In the fieUs searched

Elee»enlc data base consuMed during the irtemallonal search (name of data base and. where practical, search terms used)

CHEM ABS Data, WPI Data, EPO-Internal

C. DOCUMEMTS CONSIDERED TOBEBElgVAWT

Category • CBattoo ol document. ««h Indlcallon. where approprlale. ol the relevant passages

WO 00 21955 A (PASQUET GEORGES ;HENNEQUIN
LAURENT FRANCOIS AND (FR); ZEMECA PHARM)
20 April 2000 (2000-04-20)
examples 16-20

US 5 710 158 A (MYERS MICHAEL R
20 January 1998 (1998-01-20)

page 27

ET AL)

WO 00 39101 A (BREAULT GLORIA ANNE ; PEASE
JANET ELIZABETH (GB); ASTRAZEMECA UK LT)
6 July 2000 (2000-07-06)
examples. 135,160,161

Ftetevani to dalm Ma

1,17

1,17

1,17

□

Funher documents are listed in the contlmiallon of txix C.

Patent famBy members are llsied In ann^

* Special categories of cited documents :

*A' document defining the general stale of the art which Is not

considefed to be of particular relevance
'E* earlier document but put>llshed on or after the international

filing date

*L* document which may throw doubts on priority clalm(s)ar
which is cHed to estat>lish the publication dale of another
cttalion or other special reason (as specried)

'O* document referring to an oial d'sctosuie. use, exhibUlonor

'P" document published prior to the imemational filing date but
later than tha priority date claimed

-T* laterdocument published after the international fiUng date
or priority dale and not In confljcl with the applitaUonbul
died to understand the prindple or theoiy underiymg the
invention

•X' document of particular reiewance; the clalmBd invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone

•V document of paiticular relevance; the claimed invention

cannot be considered to Involve an inventive step when the
document is combined with one or more other such docu-
ments, such oomblnalion being obvious to a person skilled
in the art

*&* document member of the same patent family

Date of the actual completkm of the Intemallonal search

24 July 2002

Data of maifing of the International search report

01/08/2002

Hasve and mailing address of the ISA

European Patent Office. P.B. 5618 Patentlaan 2
NL-2280IHVR4Swi]k
TeL (+31-70) 340-2040. Tx. 31 651 epo nl.
Fax: (431-70) 340-3016

Authorized officer

De Jong, B

Form PCT/ISA/210 (second sheet) (July 1993)

INTERNATIONAL SEARCH REPORT

lational application No.
PCT/US 01/49140

Box I Observations where certain claims were found unsearchable (Continuation of Item 1 of first sheet)

This inlemaUonal Search Report has not been established in lespect of certain claims under Article 17{2)(a) for the following reasons:
^ * Realise mey relate to subject matter not required to be searched by this Authority, namely:

Although claims 19-3& are directed to a method of treatment of the
human/animal body, the search has been carried out and based on the alleged
effects of the compounds.

^' D teMuseSfey relate to parts of the intemaUonal Application that do not comply with the prescribed requirements to such
an extent that no meaningful Intemational Search can be carried out, specifically:

^' ^ b^se are dependem claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box II Observations where unity of invention is lacking (Continuation of Item 2 of first stieet)

This Intemational Searching Authority found multiple inventions In this intemational application, as follows:

1 . I I As all required additional search fees were timely paid l>y the applicant, this International Search Report covers an
I — I searchable claims.

2. rn As all searchable claims could be seardied without effort justifying an additional fee. this Authority cfid not bwite payment
— of any additional fee.

3 I I As only some of the required additional search fees were timely paid by the applicant, this International Search Report
> — I covers only those claims for which fees were paid, specifically claims Nos.:

4 I I Nto required adcfitional search fees were timely paid by the appUcant Consequently, this Intemalional Search Report Is
* — ^ restricted to the Invention first mentioned in the claims: it Is covered by claims IMos.:

Remark on Protest The additional search fees were accompanied by the appllcanf s protest

j j No protest accompanied the payment of additional search fees.

Form PGT/ISA/210 (oontimiation of first sheet (1)) (July 1998)

INTERNATIONAL SEARCH REPORT

Intormation en patent tamily members

Patent document -
cited in seareii report

|3ublication

UO 0021955

20-04-2000

iti

us 5710158

20-01-1998

AU
BR
CN
EP
WO
NO

US

AU

EP

SG

UO

US

US

US

US

US

US

US

AT

AU

AU

CA

DE

DE

DK

EP

ES

GR

JP

MX

SG

UO

US

Int^^onal Application No

PCT/US 01/49140

Patent ^ily
memk>6r(8)

A
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6112899
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20011739 A

5480883 A

1305095 A
0871448 Al
54172 Al

9515758 Al

RE37650

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5795889

5646153

5721237

6057320

RE36256
159009
658646

1993492

2102780 Al
69222637 Dl
69222637 12
584222 T3

0584222 Al

2108120 T3

3024955 13

6507643

9202181
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5409930 A

El

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82

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07-06-2001

02- 01-
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Ua 003M01

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06-07-2000 AU
BR

1874300 A
9916590 A

31-07-2000
23-10-2001

CN

1335838 T

13-02-2002

EP

1140860 Al

10-10-2001

UO

0039101 Al

06-07-2000

NO

20013038 A

22-08-2001

Focm PCT/ISA«10 ipaianIL famiV onnox) (July 19881